Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof

ABSTRACT

This invention relates to new oxazolidinones having a cyclopropyl moiety, which are effective against aerobic and anerobic pathogens such as multi-resistant staphylococci, streptococci and enterococci, Bacteroides spp., Clostridia spp. species, as well as acid-fast organisms such as  Mycobacterium tuberculosis  and other mycobacterial species. 
     The compounds are represented by structural formula I: 
                         
its enantiomer, diastereomer, or pharmaceutically acceptable salt or ester thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of application Ser. No. 10/878,637,filed Jun. 29, 2004, now U.S. Pat. No. 7,462,633 that claims the benefitof U.S. Provisional Application No. 60/483,904, filed Jul. 2, 2003,entitled CYCLOPROPYL GROUP SUBSTITUTED OXAZOLIDINONE ANTIBIOTICS ANDDERIVATIVES THEREOF, and U.S. Provisional Application 60/546,984, filedFeb. 24, 2004, entitled CYCLOPROPYL GROUP SUBSTITUTED OXAZOLIDINONEANTIBIOTICS AND DERIVATIVES THEREOF, which are hereby incorporatedherein by reference it their entirety.

BACKGROUND OF THE INVENTION

Oxazolidinones represent the first new class of antibacterials to bedeveloped since the quinolones. The oxazolidinones are syntheticantibacterial compounds that are orally or intravenously active againstproblematic multidrug resistant Gram positive organisms and are notcross-resistant with other antibiotics. See Riedl et al, RecentDevelopments with Oxazolidinone Antibiotics, Exp. Opin. Ther. Patents(1999) 9(5), Ford et al., Oxazolidinones: New Antibacterial Agents,Trends in Microbiology 196 Vol.5, No. 5, May 1997 and WO 96/35691. Seealso WO 03/063862, WO 01/81350, WO 01/94342, WO 03/072553, EP 0352781and U.S. Pat. Nos. 5,565,571 and 4,053,593.

This invention relates to new oxazolidinones having a cyclopropylmoiety, which are effective against aerobic and anerobic pathogens suchas multi-resistant staphylococci, streptococci and enterococci,Bacteroides spp., Clostridia spp. species, as well as acid-fastorganisms such as Mycobacterium tuberculosis and other mycobacterialspecies.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I:

its enantiomer, diastereomer, or pharmaceutically acceptable salt,hydrate or prodrug thereof wherein: R₁ represents

-   i) hydrogen,-   ii) (CH₂)_(n)NR₅R₆,-   iii) CR₇R₈R₉, C(R)₂OR₁₄, CH₂NHR₁₄,-   iv) C(═O)R₁₃, C(═NOH)H, C(═NOR₁₃)H, C(═NOR₁₃)R₁₃, C(═NOH)R₁₃,    C(═O)N(R₁₃)₂, C(═NOH)N(R₁₃)₂, NHC(═X₁)N(R₁₃)₂, NRCO₂R, (C═NH)R₇,    N(R₁₃)C(═X₁)N(R₁₃)₂, COOR₁₃, SO₂R₁₄, N(R₁₃)SO₂R₁₄, N(R₁₃)COR₁₄,-   v) (C₁₋₆alkyl)CN, CN, CH═C(R)₂, (CH₂)_(p)OH, C(═O)CHR₁₃,    C(═NR₁₃)R₁₃, NR₁₀C(═X₁)R₁₃; or-   vi) C₅₋₁₀ heterocycle optionally substituted with 1-3 groups of R₇,    which may be attached through either a carbon or a heteroatom;

X represents

or a C₅₋₁₀ heteroaryl represented by

which represents an optionally substituted aromatic heterocyclic groupcontaining 1 to 4 nitrogen atoms and at least one double bond, and whichis connected through a bond on any nitrogen said heteroaryl optionallysubstituted with 1 to 3 substitutents selected from R₇

Y represents NR*, O, CN, or S(O)p;

represents aryl or heteroaryl, heterocycle, heterocyclyl orheterocyclic;

R_(x) represents hydrogen or C₁₋₆ alkyl;

-   R₃ represent NR(C═X₂)R₁₂, NR*R₁₂, C₆₋₁₀ aryl, or —(O)_(n)C₅₋₁₀    heterocyclyl which may be attached through either a carbon or a    heteroatom; said aryl and heterocyclyl optionally substituted with    1-3 groups of R₇,

R₄, R_(4a), R_(4b), and R_(4c) independently represent

-   i) hydrogen,-   ii) halogen,-   iii) C₁₋₆ alkoxy, or-   iv) C₁₋₆ alkyl;    r and s independently are 1-3, with the provision that when    (R_(4a))_(s) and (R₄)_(r) or(R_(4b)) and (R_(4c))_(s) are attached    to an Ar or HAr ring the sum of r and s is less than or equal to 4;

R₅ and R₆ independently represent

-   -   i) hydrogen,    -   ii) C₁₋₆ alkyl optionally substituted with 1-3 groups of        halogen, CN, OH, C₁₋₆ alkoxy, amino, imino, hydroxyamino,        alkoxyamino, C₁₋₆ acyloxy, C₁₋₆ alkylsulfenyl, C₁₋₆        alkylsulfinyl, C₁₋₆ alkylsulfonyl, aminosulfonyl, C₁₋₆        alkylaminosulfonyl, C₁₋₆ dialkylam inosulfonyl,        4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl,        ethylenyloxy, or ethynyl, said phenyl and pyridine optionally        substituted with 1-3 halogen, CN, OH, CF₃, C₁₋₆ alkyl or C₁₋₆        alkoxy;    -   iii) C₁₋₆ acyl optionally substituted with 1-3 groups of        halogen, OH, SH, C₁₋₆ alkoxy, naphthalenoxy, phenoxy, amino,        C₁₋₆ acylamino, hydroxylamino, alkoxylamino, C₁₋₆ acyloxy,        aralkyloxy, phenyl, pyridine, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylamino, C₁₋₆ dialkylamino, C₁₋₆ hydroxyacyloxy, C₁₋₆        alkylsulfenyl, phthalimido, maleimido, succinimido, said        phenoxy, phenyl and pyridine optionally substituted with 1-3        groups of halo, OH, CN, C₁₋₆ alkoxy, amino, C₁₋₆ acylamino, CF₃        or C₁₋₆ alkyl;    -   iv) C₁₋₆ alkylsulfonyl optionally substituted with 1-3 groups of        halogen, OH, C₁₋₆ alkoxy, amino, hydroxylamino, alkoxylamino,        C₁₋₆ acyloxy, or phenyl; said phenyl optionally substituted with        1-3 groups of halo, OH, C₁₋₆ alkoxy, amino, C₁₋₆ acylamino, CF₃        or C₁₋₆ alkyl;    -   v) arylsulfonyl optionally substituted with 1-3 of halogen, C₁₋₆        alkoxy, OH or C₁₋₆ alkyl;    -   vi) C₁₋₆ alkoxycarbonyl optionally substituted with 1-3 of        halogen, OH, C₁₋₆ alkoxy, C₁₋₆ acyloxy, or phenyl, said phenyl        optionally substituted with 1-3 groups of halo, OH, C₁₋₆ alkoxy,        amino, C₁₋₆ acylamino, CF₃ or C₁₋₆ alkyl;    -   vii) aminocarbonyl, C₁₋₆ alkylaminocarbonyl or C₁₋₆        dialkylaminocarbonyl, said alkyl groups optionally substituted        with 1-3 groups of halogen, OH, C₁₋₆ alkoxy or phenyl    -   viii) five to six membered heterocycles optionally substituted        with 1-3 groups of halogen, OH, CN, amino, C₁₋₆ acylamino, C₁₋₆        alkylsulfonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkoxy, C₁₋₆        acyloxy or C₁₋₆ alkyl, said alkyl optionally substituted with        1-3 groups of halogen, or C₁₋₆ alkoxy;    -   ix) C₃₋₆ cycloalkylcarbonyl optionally substituted with 1-3        groups of halogen, OH, C₁₋₆ alkoxy or CN;    -   x) benzoyl optionally substituted with 1-3 groups of halogen,        OH, C₁₋₆ alkoxy, C₁₋₆ alkyl, CF₃, C₁₋₆ alkanoyl, amino or C₁₋₆        acylamino;    -   xi) pyrrolylcarbonyl optionally substituted with 1-3 of C₁₋₆        alkyl;    -   xii) C₁₋₂ acyloxyacetyl where the acyl is optionally substituted        with amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, 4-morpholino,        4-aminophenyl, 4-(dialkylamino)phenyl, 4-(glycylamino)phenyl; or

R₅ and R₆ taken together with any intervening atoms can form a 3 to 7membered heterocyclic ring containing carbon atoms and 1-2 heteroatomsindependently chosen from O, S, SO, SO₂, N, or NR₈;

-   R₇ represent-   i) hydrogen, halogen, (CH₂)_(p)C₅₋₁₀ heterocyclyl, CN, CO₂R,    CON(R)₂, CHO, (CH₂)₀₋₃NHAc, C(═NOR), OH, C₁₋₆ alkoxy, C₁₋₆ alkyl,    alkenyl, hydroxy C₁₋₆ alkyl, (CH₂)₁₋₃NHC(O)C₁₋₆ alkyl,    (CH₂)₀₋₃N(C₁₋₆ alkyl)₂, NHCO₂R, —OCOC₁₋₆ alkyl;-   ii) (CH₂)_(n)amino, (CH₂)_(n)C₁₋₆ alkylamino, C₁₋₆ acylamino, C₁₋₆    dialkylamino, hydroxylamino or C₁₋₂ alkoxyamino all of which can be    optionally substituted on the nitrogen with C₁₋₆ acyl, C₁₋₆    alkylsulfonyl or C₁₋₆ alkoxycarbonyl, said acyl and alkylsulfonyl    optionally substituted with 1-2 of halogen or OH;

R₈ and R₉ independently represent

-   i) H, CN,-   ii) C₁₋₆ alkyl optionally substituted with 1-3 halogen, CN, OH, C₁₋₆    alkoxy, C₁₋₆ acyloxy, or amino,-   iii) phenyl optionally substituted with 1-3 groups of halogen, OH,    C₁₋₆ alkoxy; or

R₇ and R₈ taken together can form a 3-7 membered carbon ring optionallyinterrupted with 1-2 heteroatoms chosen from O, S, SO, SO₂, NH, and NR₈;

X₁ represents O, S or NR₁₃, NCN, NCO₂R₁₆, or NSO₂R₁₄

X₂ represents O, S, NH or NSO₂R₁₄;

R₁₀ represents hydrogen, C₁₋₆ alkyl or CO₂R₁₅;

R₁₂ represents hydrogen, C₁₋₆ alkyl, NH₂, OR, CHF₂, CHCl₂, C(R)₂Cl,(CH₂)_(n)SR, (CH₂) CN, (CH₂)_(n)SO₂R, (CH₂)_(n)S(O)R, C₁₋₆ alkylamino,C₃₋₆ cycloalkyl, C₅₋₁₀ heterocyclyl or C₁₋₆ dialkylamino, where saidalkyl, and cycloalkyl may be substituted with 1-3 groups of halo, CN, OHor C₁₋₆ alkoxy, said heterocyclyl optionally substituted with 1-3 groupsof R₇;

Each R₁₃ represents independently hydrogen, C₁₋₆ alkyl, C₆₋₁₀ aryl,NR₅R₆, SR₈, S(O)R₈, S(O)₂ R₈, CN, OH, C₁₋₆ alkylS(O)R, C₁₋₆alkoxycarbonyl, hydroxycarbonyl, —OCOaryl, C₁₋₆ acyl, C₃₋₇ memberedcarbon ring optionally interrupted with 1-4 heteroatoms chosen from O,S, SO, SO₂, NH and NR₈ where said C₁₋₆ alkyl, aryl or C₁₋₆ acyl groupsmay be independently substituted with 0-3 halogens, hydroxy, N(R)₂,CO₂R, C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, or C₁₋₆ alkoxy groups; When two R₁₃groups are attached to the same atom or two adjacent atoms they may betaken together to form a 3-7 membered carbon ring optionally interruptedwith 1-2 heteroatoms chosen from O, S, SO, SO₂, NH, and NR₈;

R represents hydrogen or C₁₋₆ alkyl;

R* represents hydrogen, CN, C(═O)R₁₄, (CH₂)_(p)CO₂C₁₋₆ alkyl,(CH₂)_(p)C₅₋₁₀heterocyclyl, or C₁₋₆ alkyl, said alkyl and heterocyclyloptionally substituted with 1 to 3 groups of R₇;

R₁₄ represents amino, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,(CH₂)_(p)C₅₋₁₀heterocyclyl, C₁₋₆ haloalkyl, phenyl, said alkyl,cycloalkyl, phenyl, heterocyclyl optionally substituted with 1-3 groupof R₇, when R₇ is an amino or hydroxyl group or a nitrogen that formspart of the heterocycle, said amino and hydroxy optionally protectedwith an amino or hydroxy protecting group;

R₁₅ is C₁₋₆ alkyl or benzyl said benzyl optionally substituted with 1-3groups of halo, OH, C₁₋₆ alkoxy, amino, C₁₋₆ acylamino, or C₁₋₆ alkyl;

R₁₆ is hydrogen, C₅₋₁₀heteroaryl, C₆₋₁₀aryl, said heteroaryl and aryloptionally substituted with 1-3 groups of R₇;

p represents 0-2 and

m, n and q independently represent 0-1.

Another aspect of the invention is concerned with the use of the novelantibiotic compositions in the treatment of bacterial infections.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described herein in detail using the terms definedbelow unless otherwise specified.

The compounds of the present invention may have asymmetric centers,chiral axes and chiral planes, and occur as racemates, racemic mixtures,and as individual diastereomers, with all possible isomers, includingoptical isomers, being included in the present invention. (See E. L.Eliel and S. H. Wilen Stereochemistry of Carbon Compounds (John Wileyand Sons, New York 1994, in particular pages 1119-1190).

When any variable (e.g. aryl, heterocycle, R₅, R₆ etc.) occurs more thanonce, its definition on each occurrence is independent at every otheroccurrence. Also combinations of substituents/or variables arepermissible only if such combinations result in stable compounds.

The term “alkyl” refers to a monovalent alkane (hydrocarbon) derivedradical containing from 1 to 15 carbon atoms unless otherwise defined.It may be straight or branched. Preferred alkyl groups include loweralkyls which have from 1 to 6 carbon atoms such as methyl, ethyl,propyl, isopropyl, butyl and t-butyl. When substituted, alkyl groups maybe substituted with up to 3 substituent groups, selected from the groupsas herein defined, at any available point of attachment. When the alkylgroup is said to be substituted with an alkyl group, this is usedinterchangeably with “branched alkyl group”.

Cycloalkyl is a species of alkyl containing from 3 to 15 carbon atoms,without alternating or resonating double bonds between carbon atoms. Itmay contain from 1 to 4 rings which are fused. Preferred cycloalkylgroups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Whensubstituted, cycloalkyl groups may be substituted with up to 3substituents which are defined herein by the definition of alkyl.

Alkanoyl refers to a group derived from an aliphatic carboxylic acid of2 to 4 carbon atoms. Examples are acetyl, propionyl, butyryl and thelike.

The term “alkoxy” refers to those groups of the designated length ineither a straight or branched configuration and if two or more carbonatoms in length, they may include a double or a triple bond. Exemplaryof such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxyallyloxy, propargyloxy, and the like.

refers to aryl or heteroaryl, heterocycle, Het, heterocyclyl orheterocyclic as described immediately below.

Aryl refers to any stable monocyclic or bicyclic carbon ring of up to 7atoms in each ring, wherein at least one ring is aromatic. Examples ofsuch aryl elements include phenyl, napthyl, tetrahydronaphthyl, indanyl,indanonyl, biphenyl, tetralilnyl, tetralonyl, fluorenonyl, phenanthryl,anthryl, acenaphthyl, and the like substituted phenyl and the like. Arylgroups may likewise be substituted as defined. Preferred substitutedaryls include phenyl and naphthyl.

The term heterocycle, heteroaryl, Het, heterocyclyl or heterocyclic, asused herein except where noted, represents a stable 5- to 7-memberedmono- or bicyclic or stable 8- to 11-membered bicyclic heterocyclic ringsystem, any ring of which may be saturated or unsaturated, and whichconsists of carbon atoms and from one to four heteroatoms selected fromthe group consisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quatemized (in which case it is properly balanced by acounterion), and including any bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom,which results in the creation of a stable structure. The termheterocycle or heterocyclic includes heteroaryl moieties. “Heterocycle”or “heterocyclyl” therefore includes the above mentioned heteroaryls, aswell as dihydro and tetrahydro analogs thereof. The heterocycle,heteroaryl, Het or heterocyclic may be substituted with 1-3 groups ofR7. Examples of such heterocyclic elements include, but are not limitedto the following: piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl,pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl,isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl,isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl,isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl,thiophenyl, imidazopyridinyl, triazolyl, tetrazolyl, triazinyl, thienyl,benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,naphthpyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrotriazolyl, dihydrothienyl, dihydrooxazolyl,dihydrobenzothiophenyl, dihydrofuranyl, benzothiazolyl, benzothienyl,benzoimidazolyl, benzopyranyl, benzothiofuranyl, carbolinyl, chromanyl,cinnolinyl, benzopyrazolyl, benzodioxolyl and oxadiazolyl. Additionalexamples of heteroaryls are illustrated by formulas a, b, c and d:

wherein R₁₆ and R₁₇ are independently selected from hydrogen, halogen,C₁₋₆ alkyl, C_(2-∝)alkanoyl, C₁₋₆ alkoxy; and R₁₈ represents hydrogen,C₁₋₆ alkyl, C₂₋₄ alkanoyl, C₁₋₆ alkoxycarbonyl and carbamoyl.

The term “alkenyl” refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 10 carbon atoms and at least one carbon tocarbon double bond. Preferred alkenyl groups include ethenyl, propenyl,butenyl and cyclohexenyl.

The terms “quaternary nitrogen” and “positive charge” refer totetravalent, positively charged nitrogen atoms (balanced as needed by acounterion known in the art) including, e.g., the positively chargednitrogen in a tetraalkylammonium group (e.g. tetramethylammonium),heteroarylium, (e.g., N-methyl-pyridinium), basic nitrogens which areprotonated at physiological pH, and the like. Cationic groups thusencompass positively charged nitrogen-containing groups, as well asbasic nitrogens which are protonated at physiologic pH.

The term “heteroatom” means O, S or N, selected on an independent basis.

The term “prodrug” refers to compounds which are drug precursors which,following administration and absorption, release the drug in vivo viasome metabolic process. Exemplary prodrugs include acyl amides of theamino compounds of this inventon such as amides of alkanoic(C₁ ₆)acids,amides of aryl acids (e.g., benzoic acid) and alkane(C₁₋₆)dioic acids.

Halogen and “halo” refer to bromine, chlorine, fluorine and iodine.

When a group is termed “substituted”, unless otherwise indicated, thismeans that the group contains from 1 to 3 substituents thereon.

When a functional group is termed “protected”, this means that the groupis in modified form to preclude undesired side reactions at theprotected site. Suitable protecting groups for the compounds of thepresent invention will be recognized from the present application takinginto account the level of skill in the art, and with reference tostandard textbooks, such as Greene, T. W. et al. Protective Groups inOrganic Synthesis Wiley, N.Y. (1991). Examples of suitable protectinggroups are contained throughout the specification.

Examples of suitable hydroxyl and amino protecting groups are:trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, t-butyldiphenylsilyl, t-butyldimethylsilyl,benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl,allyloxycarbonyl and the like. Examples of suitable carboxyl protectinggroups are benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl,allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl,t-butyldimethylsilyl, t-butldiphenylsilyl, 2-(trimethylsilyl)ethyl,phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl,t-butyl and the like.

The cyclopropyl containing oxazolidinone compounds of the presentinvention are useful per se and in their pharmaceutically acceptablesalt and ester forms for the treatment of bacterial infections in animaland human subjects. The term “pharmaceutically acceptable ester, salt orhydrate,” refers to those salts, esters and hydrated forms of thecompounds of the present invention which would be apparent to thepharmaceutical chemist. i.e., those which are substantially non-toxicand which may favorably affect the pharmacokinetic properties of saidcompounds, such as palatability, absorption, distribution, metabolismand excretion. Other factors, more practical in nature, which are alsoimportant in the selection, are cost of the raw materials, ease ofcrystallization, yield, stability, solubility, hygroscopicity andflowability of the resulting bulk drug. Conveniently, pharmaceuticalcompositions may be prepared from the active ingredients in combinationwith pharmaceutically acceptable carriers. Thus, the present inventionis also concerned with pharmaceutical compositions and methods oftreating bacterial infections utilizing as an active ingredient thenovel cyclopropyl containing oxazolidinone compounds.

The pharmaceutically acceptable salts referred to above also includeacid addition salts. Thus, when the Formula I compounds are basic, saltsmay be prepared from pharmaceutically acceptable non-toxic acids,including inorganic or organic acids. Included among such acid salts arethe following: acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide;hydroiodide, 2-hydroxyethanesulfonate, isethionic, lactate, maleate,mandelic, malic, maleic, methanesulfonate, mucic,2-naphthalenesulfonate, nicotinate, nitric oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,phosphate, pantothenic, pamoic, sulfate, succinate, tartrate,thiocyanate, tosylate and undecanoate.

When the compound of the present invention is acidic, suitable“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable inorganicnon-toxic bases include salts of primary, secondary and teritary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betainecaffeine, choline, N,N¹-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine and the like.

The pharmaceutically acceptable esters are such as would be readilyapparent to a medicinal chemist, and include those which are hydrolyzedunder physiological conditions, such as “biolabile esters”,pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl,and others.

Biolabile esters are biologically hydrolizable, and may be suitable fororal administration, due to good absorption through the stomach orintenstinal mucosa, resistance to gastric acid degrada-tion and otherfactors. Examples of biolabile esters include compounds.

An embodiment of this invention is realized when R1 independentlyrepresent H, NR₅R₆, CN, OH, or CR₇R₈R₉ and all other variables are asdescribed herein.

Another embodiment of this invention is realized when

independently are phenyl, pyridyl, pyrimidinyl, or piperidinyl and allother variables are as described herein.

Another embodiment of this invention is realized when R₁ is CN and allother variables are as described herein.

An embodiment of this invention is realized when Y is NR* and all othervariables are as described herein.

Another embodiment of this invention is realized when X is C₅₋₁₀heteroaryl represented by

which represents an optionally substituted aromatic heterocyclic groupcontaining 1 to 4 nitrogen atoms and at least one double bond, and whichis connected through a bond on any nitrogen. Exemplary groups are1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, tetrazole, pyrazole, andimidazole, any of which may contain 1 to 3 substitutents selected fromR₇.

Another embodiment of this invention is realized when X is

and all other variables are as described herein. A sub-embodiment ofthis invention is realized when Y is NR* and R₁ is CN or NH₂.

Another embodiment of this invention is realized when R₃ is C₅₋₁₀heteroaryl, said heteroaryl optionally substituted with 1-3 groups of R₇and all other variables are as described herein.

Another embodiment of this invention is realized when R₃ is a C₅₋₁₀heteroaryl represented by

which represents an optionally substituted aromatic heterocyclic groupcontaining 1 to 4 nitrogen atoms and at least one double bond, and whichis connected through a bond on any nitrogen. Exemplary groups are1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, tetrazole, pyrazole, andimidazole, any of which may contain 1 to 3 substitutents selected fromR₇.

Still another embodiment of this invention is realized when R₅ and R₆independently are:

-   i) H,-   ii) C₁₋₆ alkyl optionally substituted with 1-3 groups of halogen,    CN, OH, C₁₋₆ alkoxy, amino, hydroxyamino, alkoxyamino, C₁₋₆ acyloxy,    C₁₋₆ alkylsulfenyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,    aminosulfonyl, C₁₋₆ alkylaminosulfonyl, C₁₋₆ dialkylaminosulfonyl,    4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl, ethyenyloxy,    or ethynyl, said phenyl and pyridine optionally substituted with 1-3    halogen, CN, OH, CF3, C₁₋₆ alkyl or C₁₋₆ alkoxy;-   iii) C₁₋₆ acyl optionally substituted with 1-3 groups of halogen,    OH, SH, C₁₋₆ alkoxy, naphthalenoxy, phenoxy, amino, C₁₋₆ acylamino,    hydroxylamino, alkoxylamino, C₁₋₆ acyloxy, phenyl, pyridine, C₁₋₆    alkylcarbonyl, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆    hydroxyacyloxy, C₁₋₆ alkylsulfenyl, phthalimido, maleimido,    succinimido, said phenoxy, phenyl and pyridine optionally    substituted with 1-3 groups of halo, OH, CN, C₁₋₆ alkoxy, amino,    C₁₋₆ acylamino, CF₃ or C₁₋₆ alkyl; or-   iv) benzoyl optionally substituted with 1-3 groups of halogen, OH,    C₁₋₆ alkoxy, C₁₋₆ alkyl, CF₃, C₁₋₆ alkanoyl, amino or C₁₋₆ acylamino    and all other variables are as described herein.

Yet another embodiment of this invention is realized when X₁ representsO and all other variables are as described herein.

A preferred embodiment of this invention is realized when the structuralformula is III:

wherein R₄, R_(4a), and R₃ are as described herein and

is 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, tetrazole, pyrazole,or imidazole, any of which may contain 1 to 3 substitutents selectedfrom R₇.

A subembodiment of this invention is realized when R3 is a C₅₋₁₀heteroaryl represented by

which represents an optionally substituted aromatic heterocyclic groupcontaining 1 to 4 nitrogen atoms and at least one double bond, and whichis connected through a bond on any nitrogen.

Another preferred embodiment of this invention is realized when thestructural formula is IV:

wherein R₁, R₄, R_(4a), Y and R₃ are as described herein. Asubembodiment of this invention is realized when R3 is a C₅₋₁₀heteroaryl represented by

which represents an optionally substituted aromatic heterocyclic groupcontaining 1 to 4 nitrogen atoms and at least one double bond, and whichis connected through a bond on any nitrogen.

Preferred compounds of this invention are:

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazolehydrochloride,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazolehydrochloride,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazolehydrochloride,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-ooxazolidin-5-ylmethyl]-1,2,3-triazolehydrochloride,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamidehydrochloride,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamidehydrochloride,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamidehydrochloride,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamidehydrochloride,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

-   N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[3-Fluoro-4-[2-(1-methyltetrazol-5-yl)pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[3,5-Difluoro-4-[2-(1-methyltetrazol-5-yl)pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamidehydrochloride,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamidehydrochloride,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]phenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]phenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazolehydrochloride,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]phenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]phenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamideS-oxide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamideS,S-dioxide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-oxide,

1-[5(R)-3-[4-[2-[((1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-dioxide,

4-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,4-triazole,

4-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-S-ylmethyl]-1,2,4-triazole,

5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-one,

5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-one,

5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazol-3-yl)]aminomethyloxazolidin-2-one,

5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[N-(isoxazol-3-yl)]aminomethyloxazolidin-2-one,

5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-one,

5(R)-5-[N-(t-butoxycarbonyl)-N-(isoxazol-3-yl)]aminomethyl-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one,

5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[N-(isoxazol-3-yl)]aminomethyloxazolidin-2-one,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]propionamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]cyclopropanecarboxamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]propionamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]propionamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]cyclopropanecarboxamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]cyclopropanecarboxamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3,6-dicyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[(1-t-butoxycarbonylaminocyclopropan-1-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[(1-aminocyclopropan-1-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-[2-(phthalimid-2-yl)ethyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-(2-aminoethyl)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-[2-(1,2,4-triazol-4-yl)ethyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-bromoacetyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-(morpholin-4-yl)acetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-(5-cyanopyridin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-(1,3-dihydroxypropan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S)-1-t-butoxycabonylpyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ymethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-[((2S)-pyrrolidin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S,4R)-1-t-butoxycabonyl-4-hydroxypyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-[((2S,4R)-4-hydroxypyrrolidin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S,4S)-1-t-butoxycabonyl-4-fluoropyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-[((2S,4S)-4-fluoropyrrolidin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-amino-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoledihydrochloride,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-acetoxyacetyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-hydroxyacetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-dichlorocyclopropane)-1-carboxamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-dichlorocyclopropane)-1-carboxamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-dichlorocyclopropane)-1-carboxamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-difluorocyclopropane)-1-carboxamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-difluorocyclopropane)-1-carboxamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-difluorocyclopropane)-1-carboxamide,

O-methyl-N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]carbamate,

O-methyl-N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]carbamate,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3,6-dicyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[3-fluoro-4-[2-[(1α,5α,6β)-6-hydroxymethyl-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-4-fluoro-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-4-fluoro-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-4-fluoro-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-5-fluoro-1,2,3-triazole,

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-5-fluoro-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-(4-t-butoxycarbonylpiperazin-1-yl)acetyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-(piperazin-1-yl)acetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoledihydrochloride,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]thiophen-4-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-(piperidin-1-yl)acetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-(pyrrolidin-1-yl)acetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-(4-dimethylaminopiperidin-1-yl)acetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S)-1-t-butoxycabonylpyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-[((2S)-pyrrolidin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-[((2S,4R)-4-hydroxypyrrolidin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazolehydrochloride,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S,4R)-1-t-butoxycabonyl-4-hydroxypyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S,4S)-1-t-butoxycabonyl-4-fluoropyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-[((2S,4S)-4-fluoropyrrolidin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-amino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-oxide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-amino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-oxide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-dioxide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-amino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-dioxide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-amino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-oxide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-amino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-oxide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-dioxide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-amino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-dioxide,

5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-one,

5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-one,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-(4-methylpiperazin-1-yl)acetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-oxide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-dioxide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

-   -   1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole        S-oxide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole S,S-dioxide,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-(1,3-diacetoxypropan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[(3R,4S)-1-azabicyclo[2.2.1]hepan-3-yl]carbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-(pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazol-3-yl)]aminomethyloxazolidin-2-one,

5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-5-[N-(isoxazol-3-yl)]aminomethyloxazolidin-2-one,

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-(thiatriazol-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide,

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]isothiocyanate,

O-methyl-N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate,

O-methyl-N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate,or their enantiomer, diastereomer, or pharmaceutically acceptable salt,hydrate or prodrug thereof.

Suitable subjects for the administration of the formulation of thepresent invention include mammals, primates, man, and other animals. Invitro antibacterial activity is predictive of in vivo activity when thecompositions are administered to a mammal infected with a susceptiblebacterial organism.

Using standard susceptibility tests, the compositions of the inventionare determined to be active against MRSA and enterococcal infections.

The compounds of the invention are formulated in pharmaceuticalcompositions by combining the compounds with a pharmaceuticallyacceptable carrier. Examples of such carriers are set forth below.

The compounds may be employed in powder or crystalline form, in liquidsolution, or in suspension. They may be administered by a variety ofmeans; those of principal interest include: topically, orally andparenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Theinjectable compositions may take such forms as suspensions, solutions,or emulsions in oily or aqueous vehicles, and may contain variousformulating agents. Alternatively, the active ingredient may be inpowder (lyophilized or non-lyophilized) form for reconstitution at thetime of delivery with a suitable vehicle, such as sterile water. Ininjectable compositions, the carrier is typically comprised of sterilewater, saline or another injectable liquid, e.g., peanut oil forintramuscular injections. Also, various buffering agents, preservativesand the like can be included.

Topical applications may be formulated in carriers such as hydrophobicor hydrophilic bases to form ointments, creams, lotions, in aqueous,oleaginous or alcoholic liquids to form paints or in dry diluents toform powders.

Oral compositions may take such forms as tablets, capsules, oralsuspensions and oral solutions. The oral compositions may utilizecarriers such as conventional formulating agents, and may includesustained release properties as well as rapid delivery forms.

The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated, the route and frequencyof administration, the sensitivity of the pathogen to the particularcompound selected, the virulence of the infection and other factors.Such matters, however, are left to the routine discretion of thephysician according to principles of treatment well known in theantibacterial arts. Another factor influencing the precise dosageregimen, apart from the nature of the infection and peculiar identity ofthe individual being treated, is the molecular weight of the compound.

The novel antibiotic compositions of this invention for human deliveryper unit dosage, whether liquid or solid, comprise from about 0.01% toas high as about 99% of the cyclopropyl containing oxazolidinonecompounds discussed herein, the preferred range being from about 10-60%and from about 1% to about 99.99% of one or more of other antibioticssuch as those discussed herein, preferably from about 40% to about 90%.The composition will generally contain from about 125 mg to about 3.0 gof the cyclopropyl containing oxazolidinone compounds discussed herein;however, in general, it is preferable to employ dosage amounts in therange of from about 250 mg to 1000 mg and from about 200 mg to about 5 gof the other antibiotics discussed herein; preferably from about 250 mgto about 1000 mg. In parenteral administration, the unit dosage willtypically include the pure compound in sterile water solution or in theform of a soluble powder intended for solution, which can be adjusted toneutral pH and isotonic.

The invention described herein also includes a method of treating abacterial infection in a mammal in need of such treatment comprisingadministering to said mammal the claimed composition in an amounteffective to treat said infection.

Oxazolidinones have been known at times to cause side effects such assideroblastic anemia, peripheral sensory neuropathy, optic neuropathy,seizures, thrombocytopenia, cheilosis, seborrheic dermatitis,hypo-regenerative anemia, megaloblastic anemia or normocytic anemia. Thecompounds of the invention may be combined with an effective amount ofone or more vitamins to prevent or reduce the occurrence ofoxazolidinone-associated side effects in patients. The vitamins that canbe combined are vitamin B2, vitamin B6, vitaimin B12 and folic acid. Thevitamins may be administered with the oxazolidinones as separatecompositions or the vitamins and oxazolidinones may be present in thesame composition.

Thus another aspect of this invention is a method of treating orpreventing an oxazolidinone-associated side effect by administering aneffective amount of the oxazolidinone of structural formula I and aneffective amount of one or more of vitamin B2, vitamin B6, vitaimin B12and folic acid to a patient in need thereof.

A further aspect of this invention relates to a method of treating orpreventing oxazolidinone-associated normocyctic anemia or peripheralsensory neuropathy by administering an effective amount of vitamin B2 toa patient in need thereof.

Yet another aspect of this invention relates to a method of treating orpreventing oxazolidinone-associated sideroblastic anemia, peripheralsensory neuropathy, optic neuropathy, seizures, thrombocytopenia,cheilosis, and seborrheic dermatitis by administering an effectiveamount of vitamin B6 to a patient in need thereof.

Still another aspect of this invention relates to a method of treatingor preventing oxazolidinone-associated hypo-regenerative anemia,megaloblastic anemia by administering an effective amount of vitamin B12and folic acid to a patient in need thereof.

Still another aspect of this invention relates to a method of treatingor preventing bacterial infection by administering an effective amountof a compound of formula I and an effective amount of one or more of thegroup selected from the group consisting of vitamin B2, vitamin B6,vitaimin B12 and folic acid to a patient in need thereof.

The preferred methods of administration of the claimed compositionsinclude oral and parenteral, e.g., i.v. infusion, i.v. bolus and i.m.injection formulated so that a unit dosage comprises a therapeuticallyeffective amount of each active component or some submultiple thereof.

For adults, about 5-50 mg/kg of body weight, preferably about 250 mg toabout 1000 mg per person of the cyclopropyl containing oxazolidinoneantibacterial compound and about 250 mg, to about 1000 mg per person ofthe other antibiotic(s) given one to four times daily is preferred. Morespecifically, for mild infections a dose of about 250 mg two or threetimes daily of the cyclopropyl containing oxazolidinone antibacterialcompound and about 250 mg two or three times daily of the otherantibiotic is recommended. For moderate infections against highlysusceptible gram positive organisms a dose of about 500 mg each of thecyclopropyl containing oxazolidinone and the other antibiotics, three orfour times daily is recommended. For severe, life-threatening infectionsagainst organisms at the upper limits of sensitivity to the antibiotic,a dose of about 500-2000 mg each of the cyclopropyl-containingoxazolidinone compound and the other antibiotics, three to four timesdaily may be recommended.

For children, a dose of about 5-25 mg/kg of body weight given 2, 3, or 4times per day is preferred; a dose of 10 mg/kg is typically recommended.

The compounds of the present invention can be prepared according to theprocedures of the following scheme and general examples, usingappropriate materials, and are further exemplified by the followingspecific examples. The compounds illustrated in the examples are not,however, to be construed as forming the only genus that is considered asthe invention. The following examples further illustrate details for thepreparation of compounds of the present invention. Those skilled in theart will readily understand that known variations of the conditions andprocesses of the following preparative procedures can be used to preparethe compounds of the present invention. All temperatures are in degreesCelsius unless otherwise noted.

The compounds of the present invention can be prepared according toScheme I, using appropriate materials, and are further exemplified bythe following specific examples. The compounds illustrated in theexamples are not, however, to be construed as forming the only genusthat is considered as the invention. The following examples furtherillustrate details for the preparation of compounds of the presentinvention. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare the compounds of the presentinvention. All temperatures are in degrees Celsius unless otherwisenoted.

In step 1 aromatic or heteroaromatic amines are converted to thecorresponding 5-hydroxyoxazolidinones by methods well known to thoseskilled in the art. Typical conditions include acylation of the aminewith a benzyloxycarbonyl chloride to afford the corresponding carbamatewhich is then deprotonated with a suitable strong base such n-butyllithium, lithium t-butoxide or the like and the resulting anion quenchedwith the requisite glycidylbutyrate or other suitable glycidyl ester.Upon workup and purification the hydroxymethyloxazolidinone is obtained.It will be recognized to one skilled in the art that the requisiteacylation may be catalyzed at the discretion of the experimenter by anumber of suitable organic or inorganic bases and that likewise a numberof suitable acylating agents can be envisaged for the performance ofstep 1. Moreover it should also be noted that if step 1 is performedusing an R-glycidyl ester then the resulting 5-hydroxymethyloxazolidinone will the S-configuration while performance of step 1 withan S-glycidyl ester will result in a 5-hydroxymethyl oxazolidinone withthe R-configuration.

In step 2 the aromatic ring is halogenated using a suitableelectrophilic halogenating agent undaer appropriate conditions. Anexample of such a halogenationg agent is iodine monochloride, but oneskilled in the art will be quick to recognize that other halogenatingagents could be used. One will recognize that if the desired halogen isan iodide, then an iodinating agent will be used but if another halogenis desired, then an appropriate halogenating agent will need to bechosen. These are well known to those of only ordinary skill in the art.

Step 3 describes the modification of the hydroxyl group to the R₃substituent as described in the specification. It will be recognizedthat the exact procedures, conditions, and reagents will vary dependingon the precise chemical nature of the R₃ substituent desired andrepresentative transformations are described, but not limited to, thosein the specific examples.

Step 4 describes the conversion of the aromatic halogen to a suitableboronate or boronic acid which is a suitable precursor for thesubsequent coupling to AR or HAr a. These conditions are well known toone skilled in the art and include treatment of the starting halide withbispinacolato diboron or another suitable boron precursor in thepresence of an appropriate Pd(II) catalyst such as[bis-(diphenylphosphino)ferrocene] palladium II dichloride methylenechloride complex or the like and a suitable base.

Step 5 describes the coupling of the HAr(or AR)b component with asuitable HAr(or AR)a component as detailed in the specification . Thistransformation, commonly referred to a Suzuki coupling by this skilledin the art is catalyzed by a palladium (0) species such astetrakis(triphenylphosphine)palladium (0) in the presence ao a suitablebase such as alkali metal carbonate to give the compounds iof thepresent invention. Subsequent chemical transformations, well known tothose skilled in the art, can be used to interconvert various members ofthe broad genus described and delineated as X in the specification.

The invention is further described in connection with the followingnon-limiting examples.

EXAMPLE 1

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The mixture of1-[5(R)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg),1-bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorobenzene(19.7 mg) and tetrakis(triphenylphosphine)palladium (0) (6.2 mg) indioxane (0.5 mL) and 2M sodium carbonate solution (135 μL) was heated at80° C. for 4 hours. The mixture was diluted with ethyl acetate andwashed with saturated sodium hydrogencarbonate solution. The organicextracts were washed with brine, dried over anhydrous magnesium sulfate,and then concentrated in vacuo. Preparative thin-layer chromatography(silica, ethyl acetate: acetone=9:1) of the residue gave title compound1 (19.4 mg)

MS (FAB⁺) m/z: 545 (MH⁺).

HRMS (FAB⁺) for C₂₉H₃₀FN₆O₄ (MH⁺): calcd, 545.2313; found, 545.2341.

EXAMPLE 2

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

To a solution of1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(316 mg) in dichloromethane-methanol (10:1) solution (2.5 mL) was addeda solution of hydrogen chloride in dioxane (4M, 2.5 mL) was stirred atroom temperature for 3.5 hours, then concentrated in vacuo. Treatmentwith ethanol of the residue gave title compound 2 (236 mg).

MS (FAB⁺) m/z: 445 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₄H₂₂FN₆O₂ (MH⁺): calcd, 445.1788; found, 445.1765.

EXAMPLE 3

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title compound 3 (22.3 mg) was prepared from1-[5(R)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) and5-bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridine(19.7 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 528 (MH⁺).

HRMS (FAB⁺) for C₂₈H₃₀N₇O₄ (MH⁺): calcd, 528.2359; found, 528.2352.

EXAMPLE 4

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

To a solution of1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(209 mg) in dichloromethane-methanol (10:1) solution (1.7 mL) was addeda solution of hydrogen chloride in dioxane (4M, 1.7 mL), the mixture wasstirred at room temperature for 2.5 hours, then concentrated in vacuo.After dilution of the residue with dichloromethane-methanol (10:1)solution, the mixture was made to alkaline by the addition of 2 N sodiumhydroxide solution. The resulting mixture was extracted withdichloromethane-methanol (10:1) solution. The organic extracts weredried over anhydrous magnesium sulfate, and then concentrated in vacuo.Flash chromatography (silica, dichloromethane: methanol=10:1) of theresidue gave title compound 5 (134 mg).

EXAMPLE 5

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

To a solution of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(287 mg) in dichloromethane-methanol (10:1) solution (2.5 mL) was addeda solution of hydrogen chloride in dioxane (4M, 168 μL) at 0° C., themixture was concentrated in vacuo. Treatment of the residue with ethanolgave title compound 5 (292 mg).

MS (EI⁺) m/z: 428 (M⁺) (as free base).

HRMS (EI⁺) for C₂₃H₂₂N₇O₂ (M⁺): calcd, 428.1835; found, 428.1848.

EXAMPLE 6

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The title compound 6 was prepared from1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) and1-bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorobenzene(19.6 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 563 (MH⁺).

HRMS (FAB⁺) for C₂₉H₂₉F₂N₆O₄ (MH⁺): calcd, 563.2218; found, 563.2222.

EXAMPLE 7

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

Title compound 7 (212 mg) was prepared from1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(273 mg) in the same manner as described for EXAMPLE 2.

MS (EI⁺) m/z: 462 (M⁺) (as free base).

HRMS (EI⁺) for C₂₄H₂₀F₂N₆O₂ (M⁺): calcd, 462.1616; found, 462.1631.

EXAMPLE 8

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The title compound 8 (15.8 mg) was prepared from1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) and5-bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridine(18.8 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 546 (MH⁺).

HRMS (FAB⁺) for C₂₈H₂₉FN₇O₄ (MH⁺): calcd, 546.2265; found, 546.2247.

EXAMPLE 9

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

The title compound 9 (278 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(500 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 446 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₃H₂₁FN₇O₂(MH+): calcd, 446.1741; found, 446.1733.

EXAMPLE 10

N-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound 10 (24.9 mg) was prepared fromN-[5(S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(18.9 mg) and1-bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorobenzene(20.0 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 535 (MH⁺).

HRMS (FAB⁺) for C₂₉H₃₂FN₄O₅ (MH⁺): calcd, 535.2357; found, 535.2375.

EXAMPLE 11

N-[5(S)-3-[4-[4-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamideHydrochloride.

The title compound 11 (281 mg) was prepared fromN-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(360 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 435 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₄H₂₄FN₄O₃ (MH+): calcd, 435.1832; found, 435.1821.

EXAMPLE 12

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound 12 (20.3 mg) was prepared fromN-[5(S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(20.0 mg) and5-bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridine(20.2 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 518 (MH⁺).

HRMS (FAB⁺) for C₂₈H₃₂N₅O₅ (MH⁺): calcd, 518.2403; found, 518.2412.

EXAMPLE 13

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide Hydrochloride.

The title compound 13 (254 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(366 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 418 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₃H₂₄N₅O₃ (MH⁺): calcd, 418.1879; found, 418.1885.

EXAMPLE 14

N-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound 14 (24.9 mg) was prepared fromN-[5(S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(20.0 mg) and1-bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorobenzene(20.2 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 553 (MH⁺).

HRMS (FAB⁺) for C₂₉H₃₁F₂N₄O₅ (MH⁺): calcd, 553.2263; found, 553.2250.

EXAMPLE 15

N-[5(S)-3-[4-[4-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamideHydrochloride.

The title compound 15 (290 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(367 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 453 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₄H₂₃F₂N₄O₃ (MH⁺): calcd, 453.1738; found, 453.1747.

EXAMPLE 16

N-[5(S)-3-[4-[2[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound 16 (354 mg) was prepared fromN-[5(S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(350 mg) and5-bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridine(337 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 536 (MH⁺).

HRMS (FAB⁺) for C₂₈H₃₁FN₅O₅ (MH⁺): calcd, 536.2309; found, 536.2296.

EXAMPLE 17

N-[5(S)-3-[4-[2-[(1α,5α,5β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamideHydrochloride.

The title compound 17 (259 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(400 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 436 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₃H₂₃FN₅O₃ (MH⁺): calcd, 436.1785; found, 436.1776.

EXAMPLE 18

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-t-Butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound 18 (62.7 mg) was prepared fromN-[5(S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(67.2 mg) and5-bromo-2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(63.1 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 527 (MH⁺).

HRMS (FAB⁺) for C₂₇H₃₂FN₄O₆ (MH⁺): calcd, 527.2306; found, 527.2329.

EXAMPLE 19

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a solution ofN-[5(S)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(52.0 mg) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5mL) at 0° C., the mixture was stirred at room temperature for 2 hours.After quenching the reaction by addition of saturated sodiumhydrogencarbonate solution, the mixture was extracted withchloroform-methanol (9:1) solution. The organic extracts were dried overanhydrous magnesium sulfate, and then concentrated in vacuo. Flashchromatography (NH silica, dichloromethane:methanol=20:1) of the residuegave title compound 19 (36.7 mg).

MS (EI⁺) m/z: 426 (M⁺).

HRMS (EI⁺) for C₂₂H₂₃FN₄O₄(M⁺): calcd, 426.1703; found, 426.1741.

EXAMPLE 20

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-Butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The title compound 20 (71.1 mg) was prepared from1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(65.6 mg) and5-bromo-2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(60.0 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 537 (MH⁺).

HRMS (FAB⁺) for C₂₇H₃₀FN₆O₅ (MH⁺): calcd, 537.2262; found, 537.2276.

EXAMPLE 21

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The title compound 21 (238 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(433 mg) in the same manner as described for EXAMPLE 18.

MS (FAB⁺) m/z: 437 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₂FN₆O₃ (MH⁺): calcd, 437.1737; found, 437.1755.

EXAMPLE 22

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound 22 (302 mg) was prepared fromN-[5(S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(378 mg) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(337 mg) in the same manner as described for EXAMPLE 1.

MS (EI⁺) m/z: 436 (M⁺).

HRMS (EI⁺) for C₂₃H₂₁FN₄O₄ (M⁺): calcd, 436.1547; found, 436.1516.

EXAMPLE 23

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The title compound 23 (353 mg) was prepared from1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(388 mg) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(265 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 447 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₀FN₆O₃ (MH⁺): calcd, 447.158 1; found, 447.1589.

EXAMPLE 24

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-t-Butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound 24 (387 mg) was prepared fromN-[5(S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(406 mg) and5-bromo-2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(400 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 509 (MH⁺).

HRMS (FAB⁺) for C₂₇H₃₃N₄O₆ (MH⁺): calcd, 509.2400; found, 509.2384.

EXAMPLE 25

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound 25 (262 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (380 mg) in the same manneras described for EXAMPLE 18.

MS (FAB⁺) m/z: 409 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₅N₄O₄ (MH⁺): calcd, 409.1876; found, 409.1838.

EXAMPLE 26

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-Butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The title compound 26 (313 mg) was prepared from1-[5(R)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(418 mg) and5-bromo-2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(400 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 519 (MH⁺).

HRMS (FAB⁺) for C₂₇H₃₁N₆O₅ (MH⁺): calcd, 519.2356; found, 519.2382.

EXAMPLE 27

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The title compound 27 (210 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]bexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-S-ylmethyl]-1,2,3-triazole(310 mg) in the same manner as described for EXAMPLE 18.

MS (FAB⁺) m/z: 419 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₃N₆O₃ (MH+): calcd, 419.1832; found, 419.1835.

EXAMPLE 28

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The title compound 28 (318 mg) was prepared fromN-[5(S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(360 mg) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(265 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 419 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₃N₄O₄ (MH⁺): calcd, 419.1719; found, 419.1712.

EXAMPLE 29

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The title compound 29 (344 mg) was prepared from1-[5(R)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(419 mg) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(300 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 429 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₁N₆O₃ (MH⁺): calcd, 429.1675; found, 429.1677.

EXAMPLE 30

1-[5(R)-3-[3-Fluoro-4-[2-(1-methyltetrazol-5-yl)pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The title compound 30 (480 mg) was prepared from1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(500 mg) and 5-bromo-2-(1-methyltetrazol-5-yl)pyridine (309 mg) in thesame manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 422 (MH⁺).

HRMS (FAB⁺) for C₁₉H₁₇FN₉O₂(MH⁺): calcd, 422.1489; found, 422.1508.

EXAMPLE 31

1-[5(R)-3-[3,5-Difluoro-4-[2-(1-methyltetrazol-5-yl)pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The mixture of 5-bromo-2-(1-methyltetrazol-5-yl)pyridine (312 mg),bis(pinacolato)diboron (363 mg), potassium 2-ethylhexanoate (355 mg) and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride-dichloromethane adduct (53.1 mg) in dioxane (13 mL) wasstirred at 80° C. for 1.5 hours and concentrated in vacuo. To a solutionof the resulting residue in dioxane (29 mL) was added1-[5(R)-3-[3,5-difluoro-4-(trifluoromethanesulfonyl)oxyphenyl]-2-oxooxazolidin-5-ymethyl]-1,2,3-triazole(500 mg), tetrakis(triphenylphosphine)palladium (0) (135 mg) and 2Msodium carbonate solution (2.9 mL), the mixture was stirred at 90° C.for 6 hours. Flash chromatography (NH silica, ethyl acetate) of themixture gave title compound 31 (246 mg).

MS (FAB⁺) m/z: 440 (MH⁺).

HRMS (FAB⁺) for C₁₉H₁₆F₂N₉O₂ (MH⁺): calcd, 440.1395; found, 440.1395.

EXAMPLE 32

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title compound 32 (362 mg) was prepared from1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(260 mg) and 1-bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorobenzene(267 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 581 (MH⁺).

HRMS (FAB⁺) for C₂₉H₂₈F₃N₆O₄ (MH⁺): calcd, 581.2124; found, 581.2149.

EXAMPLE 33

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

Title Compound 33 (281 mg) was prepared from1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(360 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 481 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₄H₂₀F₃N₆O₂(MH⁺): calcd, 481.1600; found, 481.1598.

EXAMPLE 34

N-[5(S)-3-[4-[2-[(1a,5a,6p)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Title Compound 34 (15.5 mg) was prepared fromN-[5(S)-3-[3,5-difluoro-4-(trifluoromethane-sulfonyl)oxyphenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(19.6 mg) and5-bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridine(20.0 mg) in the same manner as described for EXAMPLE 31.

MS (FAB⁺) m/z: 554 (MH⁺).

HRMS (FAB⁺) for C₂₈H₃₀F₂N₅O₅ (MH⁺): calcd, 554.2215; found, 554.2201.

EXAMPLE 35

(1α,5α,6β)-N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamideHydrochloride.

Title Compound 35 (185 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(235 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 454 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₃H₂₂F₂N₅O₃ (MH⁺): calcd, 454.1691,; 454.1651.

EXAMPLE 36

N-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Title Compound 36 (347 mg) was prepared fromN-[5(S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(300 mg) and1-bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorobenzene(317 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 571 (MH⁺).

HRMS (FAB⁺) for C₂₉H₃₀F₃N₄O₅ (MH⁺): calcd, 571.2168; found, 571.2159.

EXAMPLE 37

N-[5(S)-3-[4-[4-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamideHydrochloride.

Title Compound 37 (251 mg) was prepared fromN-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo-[3.1.0]hexan-6-yl]-3,5-difluorophenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(347 mg) in the same manner as described for EXAMPLE 2.

MS (EI⁺) m/z: 470 (M⁺) (as free base).

HRMS (EI⁺) for C₂₄H₂₁F₃N₄O₃ (M⁺): calcd, 470.1566; found, 470.1551.

EXAMPLE 38

N-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]phenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Title Compound 38 (274 mg) was preparedfromN-[5(S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(300 mg) and1-bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]benzene(288 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 535 (MH⁺).

HRMS (FAB⁺) for C₂₉H₃₂FN₄O₅ (MH⁺): calcd, 535.2357; found, 535.2325.

EXAMPLE 39

N-[5(S)-3-[4-[4-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]phenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide Hydrochloride.

Title Compound 39 (212 mg) was prepared fromN-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]phenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(274 mg) in the same manner as described for EXAMPLE 2

MS (FAB⁺) m/z: 435 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₄H₂₄FN₄O₃ (MH⁺): calcd, 435.1832; found, 435.1818.

EXAMPLE 40

N-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Title Compound 40 (427 mg) was prepared fromN-[5(S)-3-[3,5-difluoro-4-(trifluoromethanesulfonyl)oxyphenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(641 mg) and1-bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorobenzene(700 mg) in the same manner as described for EXAMPLE 31.

MS (FAB⁺) m/z: 571 (MH⁺).

HRMS (FAB⁺) for C₂₉H₃₀F₃N₄O₅ (MH⁺): calcd, 571.2168; found, 571.2134.

EXAMPLE 41

N-[5(S)-3-[4-[4-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamideHydrochloride.

Title Compound 41 (340 mg) was prepared fromN-[5(S)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(420 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 471 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₄H₂₂F₃N₄O₃ (MH⁺): calcd, 471.1644; found, 471.1611.

EXAMPLE 42

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 42 (273 mg) was prepared from1-[5(R)-3-[3,5-difluoro-4-(trifluoromethanesulfonyl)oxyphenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(561 mg) and1-bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorobenzene(600 mg) in the same manner as described for EXAMPLE 31.

MS (FAB⁺) m/z: 581 (MH⁺).

HRMS (FAB⁺) for C₂₉H₂₈F₃N₆O₄ (MH⁺): calcd, 581.2124; found, 581.2141.

EXAMPLE 43

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

Title Compound 43 1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazolehydrochloride (223 mg) was prepared from (270 mg) in the same manner asdescribed for EXAMPLE 2.

MS (FAB⁺) m/z: 481 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₄H₂₀F₃N₆O₂ (MH⁺): calcd, 481.1600; found, 481.1624.

EXAMPLE 44

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 44 (14.5 mg) was prepared from1-[5(R)-3-[3,5-difluoro-4-(trifluoromethanesulfonyl)oxyphenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(19.6 mg) and5-bromo-2-[(1a,5a,6p)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridine(20.0 mg) in the same manner as described for EXAMPLE 31.

MS (FAB⁺) m/z: 564 (MH⁺).

HRMS (FAB⁺) for C₂₈H₂₈F₂N₇O₄(MH⁺): calcd, 564.2171; found, 564.2147.

EXAMPLE 45

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

Title Compound 45 (294 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole-(360mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 464 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₃H₂₀F₂N₇O₂ (MH⁺): calcd, 464.1647; found, 464.1648.

EXAMPLE 46

1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]phenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 46 (305 mg) was prepared from1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(300 mg) and1-bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]benzene(281 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 545 (MH⁺).

HRMS (FAB⁺) for C₂₉H₃₀FN₆O₄(MH⁺): calcd, 545.2313; found, 545.2318.

EXAMPLE 47

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]phenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

Title Compound 47 (265 mg) was prepared from1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]phenyl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(305 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 445 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₄H₂₂FN₆O₂ (MH⁺): calcd, 445.1788; found, 445.1826.

EXAMPLE 48

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-Butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 48 (482 mg) was prepared from1-[5(R)-3-[3,5-difluoro-4-(trifluoromethanesulfonyl)oxyphenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(750 mg) and5-bromo-2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(684 mg) in the same manner as described for EXAMPLE 31.

MS (FAB⁺) m/z: 555 (MH⁺).

HRMS (FAB⁺) for C₂₇H₂₉F₂N₆O₅ (MH⁺): calcd, 555.2167; found, 555.2159.

EXAMPLE 49

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

To a solution of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(465 mg) in dichloromethane was added trifluoroacetic acid (4 mL) atroom temperature, the mixture was stirred at the same temperature for 1hour and concentrated in vacuo. After addition of aqueous sodiumhydrogencarbonate solution, the mixture was extracted withdichloromethane-methanol (10:1). The organic extracts were dried overanhydrous magnesium sulfate, filtered, and then concentrated in vacuo.Flash chromatography (NH silica, chloroform: methanol=9:1) of theresidue gave1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(299 mg).

MS (FAB⁺) m/z: 455 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₁F₂N₆O₃(MH⁺): calcd, 455.1643; found, 455.1649.

EXAMPLE 50

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-t-Butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Title Compound 50 (269 mg) was prepared fromN-[5(S)-3-[3,5-difluoro-4-(trifluoromethanesulfonyl)oxyphenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(500 mg) and5-bromo-2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(467 mg) in the same manner as described for EXAMPLE 31.

MS (FAB⁺) m/z: 545 (MH⁺).

HRMS (FAB⁺) for C₂₇H₃₁F₂N₄O₆ (MH⁺): calcd, 545.2212; found, 545.2224.

EXAMPLE 51

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Amino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5 -ylmethyl]acetam ide.

Title Compound 51 (278 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-oxabicyclo-[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(442 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) m/z: 445 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₃F₂N₄O₄(MH⁺): calcd, 445.1687; found, 445.1699.

EXAMPLE 52

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Title Compound 52 (349 mg) was prepared fromN-[5(S)-3-[3,5-difluoro-4-(trifluoromethanesulfonyl)oxyphenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(600 mg) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]-hexan-6-yl]pyridine(419 mg) in the same manner as described for EXAMPLE 31.

MS (FAB⁺) m/z: 455 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₁F₂N₄O₄ (MH⁺): calcd, 455.153 1; found, 455.1505.

EXAMPLE 53

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 53 (319 mg) was prepared from1-[5(R)-3-[3,5-difluoro-4-(trifluoromethanesulfonyl)oxyphenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(612 mg) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]-hexan-6-yl]pyridine(419 mg) in the same manner as described for EXAMPLE 31.

MS (FAB⁺) m/z: 465 (MH⁺).

HRMS (FAB⁺) for C₂₃H₁₉F₂N₆O₃ (MH⁺): calcd, 465.1487; found, 465.1460.

EXAMPLE 54

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Title Compound 54 (1.32 g) was prepared fromN-[5(S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(1.51 g) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-thiabicyclo-[3.1.0]hexan-6-yl]pyridine(1.13 g) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 453 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₂FN₄O₃S (MH⁺): calcd, 453.1397; found, 453.1402.

EXAMPLE 55

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamideS-Oxide.

Title Compound 55 (233 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(294 mg) in the same manner as described for EXAMPLE 58.

MS (FAB⁺) m/z: 469 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₂FN₄O₄S(MH⁺): calcd, 469.1346; found, 469.1359.

EXAMPLE 56

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamideS,S-Dioxide.

Title Compound 56 (292 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(317 mg) in the same manner as described for EXAMPLE 59.

MS (FAB⁺) m/z: 485 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₂FN₄O₅S (MH⁺): calcd, 485.1295; found, 485.1282.

EXAMPLE 57

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 57 (546 mg) was prepared from1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(582 mg) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-thiabicyclo-[3.1.0]hexan-6-yl]pyridine(422 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 463 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₀FN₆O₂S (MH⁺): calcd, 463.1352; found, 463.1355.

EXAMPLE 58

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-Oxide.

To a solution of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(118 mg) in dichloromethane-methanol (5:1, 8 mL) was added a solution ofm-chloroperoxybenzoic acid (74.5 mg) in dichloromethane-methanol (5:1, 1mL) at −19° C., the mixture was stirred at 0° C. for 70 minutes. Flashchromatography (NH silica, dichloromethane: tetrahydrofuran=7:3) of themixture gave1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-oxide (111 mg).

MS (FAB⁺) m/z: 479 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₀FN₆O₃S (MH⁺): calcd, 479.1302; found, 479.1306.

EXAMPLE 59

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-Dioxide.

To a solution of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(254 mg) in dichloromethane-methanol (5:1, 14 mL) was added a solutionof m-chloroperoxybenzoic acid (438 mg) in dichloromethane-methanol (5:1,2.0 mL) at 0° C., the mixture was stirred at room temperature for 1.25hours. After addition of m-chloroperoxybenzoic acid (146 mg) indichloromethane-methanol (5:1, 0.7 mL) to the mixture, the mixture wasstirred at room temperature for 2 hours. Flash chromatography (NHsilica, dichloromethane: tetrahydrofuran=2:1) of the mixture gave1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-dioxide (261 mg).

MS (FAB⁺) m/z: 495 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₀FN₆O₄S (MH⁺): calcd, 495.125 1; found, 495.1256.

EXAMPLE 60

4-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,4-triazole.

Title Compound 60 (64.0 mg) was prepared from5(S)-aminomethyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one (700 mg) in thesame manner as described for EXAMPLE 83.

Rf value (TLC): 0.26 (dichloromethane:methanol=10:1).

EXAMPLE 61

4-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,4-triazoleHydrochloride.

Title Compound 61 (37.9 mg) was prepared from4-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,4-triazole(64.0 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 446 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₃H₂₁FN₇O₂ (MH⁺): calcd, 446.1741; found, 446.1756.

EXAMPLE 62

5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-one.

Title Compound 62 (53.8 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one(50.0 mg) in the same manner as described for EXAMPLE 66.

MS (FAB⁺) m/z: 562 (MH⁺).

HRMS (FAB⁺) for C₂₉H₂₉FN₅O₆ (MH⁺): calcd, 562.2102; found, 562.2074.

EXAMPLE 63

5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-oneHydrochloride.

Title Compound 63 (303 mg) was prepared from5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-Azabicyclo-[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-one(400 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 462 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₄H₂₁FN₅O₄ (MH⁺): calcd, 462.1578; found, 462.1534.

EXAMPLE 64

5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazol-3-yl)]aminomethyloxazolidin-2-one.

Title Compound 64 (58.2 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo-[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one(50.0 mg) in the same manner as described for EXAMPLE 67.

MS (FAB⁺) m/z: 661 (MH⁺).

HRMS (FAB⁺) for C₃₄H₃₈FN₆O₇ (MH⁺): calcd, 661.2786; found, 661.2760.

EXAMPLE 65

5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[N-(isoxazol-3-yl)]aminomethyloxazolidin-2-oneHydrochloride.

Title Compound 65 (280 mg) was prepared from5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazol-3-yl)]aminomethyloxazolidin-2-one(600 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 461 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₄H₂₂FN₆O₃ (MH⁺): calcd, 461.1737; found, 461.1712.

EXAMPLE 66

5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-one.

To a suspension ofN-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one(200 mg), 3-hydroxyisoxazole (55.9 mg) and triphenylphosphine (199 mg)in tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (133mg), the mixture was stirred at room temperature for 1 hour, andconcentrated in vacuo. After treatment of the residue with ethyl acetateand ether, the resulting residue was dissolved in chloroform, insolublematerials were filtered off, and filtrate was concentrated in vacuo togive5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-one(205 mg).

MS (FAB⁺) m/z: 463 (MH⁺).

HRMS (FAB⁺) for C₂₄H₂₀FN₄O₅ (MH⁺): calcd, 463.1418; found, 463.1439.

EXAMPLE 67

5(R)-5-[N-(t-Butoxycarbonyl)-N-(isoxazol-3-yl)]aminomethyl-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one.

To a suspension ofN-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one(300 mg), 3-N-(t-butoxycarbonyl) aminoisoxazole (168 mg), andtetramethylazodicarboxamide (196 mg) in toluene (7.5 mL) was addedtributylphosphine (230 mg), and the mixture was stirred at 50° C. for 2hours. Flash chromatography (silica, hexane:ethyl acetate=1:1) of themixture gave5(R)-5-[N-(t-butoxycarbonyl)-N-(isoxazol-3-yl)]aminomethyl-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(392 mg).

MS (FAB⁺) m/z: 562 (MH⁺).

HRMS (FAB⁺) for C₂₉H₂₉FN₅O₆ (MH⁺): calcd, 562.2102; found, 562.2123.

EXAMPLE 68

5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[N-(isoxazol-3-yl)]aminomethyloxazolidin-2-one.

To a solution of5(R)-5-[N-(t-butoxycarbonyl)-N-(isoxazol-3-yl)]aminomethyl-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(375 mg) in dichloromethane (4.0 mL) was added trifluoroacetic acid (2.0mL) at 0° C., the mixture was stirred at room temperature for 2 hoursand then concentrated in vacuo. After dilution of the residue with ethylacetate, the mixture was washed with 5% potassium carbonate solution,dried over anhydrous magnesium sulfate, and then concentrated in vacuoto give5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-[N-(isoxazol-3-yl)]aminomethyloxazolidin-2-one(189 mg).

MS (FAB⁺) m/z: 462 (MH⁺).

HRMS (FAB⁺) for C₂₄H₂₁FN₅O₄(MH⁺): calcd, 462.1578; found, 462.1602.

EXAMPLE 69

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]propionamide.

The title Compound 69 (213 mg) was prepared from5(S)-aminomethyl-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(200 mg) in the same manner as described for EXAMPLE 70.

MS (FAB⁺) m/z: 451 (MH⁺).

HRMS (FAB⁺) for C₂₄H₂₄FN₄O₄ (MH⁺): calcd, 451.1782; found, 451.1753.

EXAMPLE 70

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide.

To a suspension of5(S)-aminomethyl-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(200 mg) in pyridine (5 mL) was added difluoroacetic anhydride (159 mg)at 0° C., the mixture was stirred at room temperature for 2 hours andthen concentrated in vacuo. After dilution of the residue withdichloromethane, the mixture was washed with 3% hydrochloric acid and 5%sodium hydrogencarbonate solution, dried over anhydrous magnesiumsulfate, and then concentrated in vacuo. Flash chromatography (silica,dichloromethane: methanol=15:1) of the residue gaveN-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide(230 mg).

MS (FAB⁺) m/z: 473 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₀F₃N₄O₄ (MH⁺): calcd, 473.1437; found, 473.1426.

EXAMPLE 71

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]cyclopropanecarboxamide.

To a solution of5(S)-aminomethyl-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(200 mg) and cyclopropanecarboxylic acid (56.8 mg) in dichloromethane(10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (146 mg) at room temperature, the mixture was stirred atthe same temperature for 2 hours. The mixture was washed with water and5% sodium hydrogencarbonate solution, dried over anhydrous magnesiumsulfate, and then concentrated in vacuo. Flash chromatography (silica,dichloromethane: methanol=15:1) of the residue gaveN-[5(S)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]cyclopropanecarboxamide(167 mg).

MS (FAB⁺) m/z: 463 (MH⁺).

HRMS (FAB⁺) for C₂₅H₂₄FN₄O₄ (MH⁺): calcd, 463.1782; found, 463.1774.

EXAMPLE 72

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]propionamide.

Title Compound 72 (305 mg) was prepared from5(S)-aminomethyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(300 mg) and propionyl chloride (58 μL) in the same manner as describedfor EXAMPLE 92.

MS (FAB⁺) m/z: 550 (MH⁺).

EXAMPLE 73

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]propionamide.

Title Compound 73 (165 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]bexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]propionamide(295 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) m/z: 450 (MH⁺).

HRMS (FAB⁺) for C₂₄H₂₅FN₅O₃ (MH⁺): calcd, 450.1941; found, 450.1905.

EXAMPLE 74

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]cyclopropanecarboxamide.

Title Compound 74 (260 mg) was prepared from5(S)-aminomethyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(300 mg) in the same manner as described for EXAMPLE 71.

MS (FAB⁺) m/z: 562 (MH⁺).

EXAMPLE 75

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]cyclopropanecarboxamide Hydrochloride.

Title Compound 75 (183 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]cyclopropanecarboxamide(250 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 462 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₅H₂₅FN₅O₃ (MH⁺): calcd, 462.194 1; found, 462.1938.

EXAMPLE 76

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide.

Title Compound 76 (258 mg) was prepared from5(S)-aminomethyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(300 mg) in the same manner as described for EXAMPLE 70.

MS (FAB⁺) m/z: 572 (MH⁺).

EXAMPLE 77

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamideHydrochloride.

Title Compound 77 (170 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide(250 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 472 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₃H₂₁F₃N₅O₃ (MH⁺): calcd, 472.1596; found, 472.1590.

EXAMPLE 78

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

To a suspension of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) in tetrahydrofuran (0.45 mL) was added acetic acid (5.1 μL),35% formaldehyde solution (35.6 μL), and sodium triacetoxyborohydride(20.0 mg) at room temperature, the mixture was stirred at the sametemperature for 3 hours. After quenching the reaction by addition ofsaturated sodium hydrogencarbonate solution at 0° C., the mixture wasextracted with dichloromethane-methanol (5:1) solution. The organicextracts were washed with brine, dried over anhydrous magnesium sulfate,and then concentrated in vacuo. Preparative thin-layer chromatography(silica, dichloromethane: methanol=10:1) of the residue gave1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(15.0 mg).

MS (FAB⁺) m/z: 460 (MH⁺).

HRMS (FAB⁺) for C₂₄H₂₃FN₇O₂ (MH⁺): calcd, 460.1897; found, 460.1888.

EXAMPLE 79

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3,6-Dicyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

A suspension of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(300 mg) and sodium acetate (390 mg) in methanol (20 mL) was stirred atroom temperature for 30 minutes. To the resulting suspension was added asolution of cyanogens bromide in dichloromethane (5 M, 0.4 mL) at 0° C.,the mixture was stirred at the same temperature for 8 hours. Afterinsoluble materials were filtered off, the filtrate was concentrated invacuo. Treatment of the residue with water and methanolgavel-[5(R)-3-[4-[2-[(1α,5α,6β)-3,6-dicyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(138 mg).

MS (FAB⁺) m/z: 471 (MH⁺).

HRMS (FAB⁺) for C₂₄H₂₀FN₈O₂ (MH⁺): calcd, 471.1693; found, 471.1709.

EXAMPLE 80

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[(1-t-Butoxycarbonylaminocyclopropan-1-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

A mixture of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg), 1-(t-butoxycarbonylamino) cyclopropane-1-carboxylic acid(13.6 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(12.9 mg), and 4-(dimethylamino)pyridine (8.2 mg) in dichloromethane wasstirred at room temperature for 5 hours. After dilution of the mixturewith water, the mixture was washed with brine, dried over anhydrousmagnesium sulfate, and then concentrated in vacuo. Flash chromatography(silica, dichloromethane: methanol=10:1) of the residue gave titlecompound 80(28.6 mg).

MS (FAB⁺) m/z: 629 (MH⁺).

HRMS (FAB⁺) for C₃₂H₃₄FN₈O₅ (MH⁺): calcd, 629.2636; found, 629.2633.

EXAMPLE 81

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[(1-Aminocyclopropan-1-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

Title Compound 81 (18.4 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[(1-t-butoxycarbonylaminocyclopropan-1-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(26.6 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 529 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₇H₂₆FN₈O₃ (MH⁺): calcd, 529.2112; found, 529.2105.

EXAMPLE 82

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-(2-Aminoethyl)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-[2-(phthalimid-2-yl)ethyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

A suspension of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg), 2-bromoethylphthalimide (11.4 mg) and potassium carbonate(9.3 mg) in acetonitrile (0.2 mL) was heated under reflux for overnightand concentrated in vacuo. Flash chromatography (silica,dichloromethane: methanol=10:1) of the residue gave compound of Step 1of Example 82 (25.2 mg).

MS (FAB⁺) m/z: 619 (MH⁺).

HRMS (FAB⁺) for C₃₃H₂₈FN₈O₄ (MH⁺): calcd, 619.2218; found, 619.2214.

Step 2.

Title compound 82

A mixture of the compound of Step 1 of Example 82 (20.0 mg) andmethylhydrazine (34.4 μL) in ethanol was heated under reflux for 2 days.After dilution of the mixture with brine, the mixture was extracted withethyl acetate. The organic extracts were dried over anhydrous magnesiumsulfate, and then concentrated in vacuo. Preparative thin-layerchromatography (NH silica, ethyl acetate: methanol=10:1) of the residuegave title compound 82 (10.8 mg).

MS (FAB⁺) m/z: 489 (MH⁺).

HRMS (FAB⁺) for C₂₅H₂₆FN₈O₂ (MH⁺): calcd, 489.2163; found, 489.2195.

EXAMPLE 83

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-[2-(1,2,4-triazol-4-yl)ethyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

A mixture of1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-(2-aminoethyl)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(29.7 mg), dimethylformamide azine (8.6 mg) and p-toluenesulfonic acid(0.6 mg) in toluene was heated under reflux for 16 hours andconcentrated in vacuo. Preparative thin-layer chromatography (silica,dichloromethane: methanol=10:1) of the residue gave title compound 83(10.9 mg).

MS (FAB⁺) m/z: 541 (MH⁺).

HRMS (FAB⁺) for C₂₇H₂₆FN₁₀O₂ (MH⁺): calcd, 541.2224; found, 541.2203.

EXAMPLE 84

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-(morphoin-4-yl)acetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-Bromoacetyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

To a solution of bromoacetyl bromide (9.8 μL) in dichloromethane (0.3mL) was added a solution of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(50.0 mg) and triethylamine (15.6 μL) in dichloromethane (1.5 mL) at 0°C., the mixture was stirred at the same temperature for 3 hours, andconcentrated in vacuo. After dilution of the residue withdichloromethane-methanol (10:1) solution, the mixture was washed with 2N hydrochloric acid, dried over anhydrous magnesium sulfate, and thenconcentrated in vacuo to give compound of Step 1 of example 84 (88.1mg).

Step 2.

Title compound 84.

To a solution of morpholine (29.3 μL) in acetonitrile (1.0 mL) was addeda solution of the crude compound of Step 1 of Example 84 (88.1 mg) inacetonitrile (1.5 mL) at 0° C., the mixture was stirred at the sametemperature for 5 hours. After dilution of the residue with water, themixture was washed with dichloromethane-methanol (10:1) solution. Theorganic extracts were washed with brine, dried over anhydrous magnesiumsulfate, and then concentrated in vacuo. Preparative thin-layerchromatography (silica, dichloromethane: methanol=5:1) of the residuegave title compound 84 (17.5 mg).

MS (FAB⁺) m/z: 573 (MH⁺).

HRMS (FAB⁺) for C₂₉H₃₀FN₈O₄ (MH⁺): calcd, 573.2374; found, 573.2381.

EXAMPLE 85

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-(5-cyanopyridin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

To a suspension of 1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) in dimethyl sulfoxide (0.5 mL) was added diisopropylethylamine(78 μL), the mixture was stirred at room temperature for 5 minutes. Tothe resulting mixture was added 2-bromo-5-cyanopyridine (16.4 mg), themixture was stirred at 60° C. for 9 hours. After dilution of the mixturewith ethyl acetate and water, the mixture was extracted with ethylacetate. The organic extracts were washed with water and brine, driedover anhydrous magnesium sulfate, filtered, and then concentrated invacuo. Flash chromatography (silica, dichloromethane:methanol=20:1) ofthe residue gave title compound 85 (12.8 mg).

MS (FAB⁺) m/z: 548 (MH⁺).

HRMS (FAB⁺) for C₂₉H₂₃FN₉O₂(MH⁺): calcd, 548.1959; found, 548.1984.

EXAMPLE 86

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-(1,3-dihydroxypropan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

To a solution of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(50.0 mg) in dichloromethane-methanol (10:1, 1.0 mL) was added1,3-dihydroxyacetone dimmer (60.7 mg), methanol (4.0 mL), acetic acid(0.5 mL), and sodium cyanoborohydride (21.2 mg), the mixture was stirredat room temperature for 7.5 hours. After addition of 2 N hydrochloricacid, the mixture was stirred at room temperature for 1 hour. Themixture was diluted with brine and extracted withdichloromethane-methanol (10:1). The organic extracts were dried overanhydrous potassium carbonate, filtered, and then concentrated in vacuo.Preparative thin-layer chromatography (silica,dichloromethane:methanol=10:1) of the residue gave title compound 86(13.2 mg).

MS (FAB⁺) m/z: 520 (MH⁺).

HRMS (FAB⁺) for C₂₆H₂₇FN₇O₄ (MH⁺): calcd, 520.2109; found, 520.2086.

EXAMPLE 87

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-[((2S)-pyrrolidin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S)-1-t-Butoxycarbonylpyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The compound of Step 1 in Example 87 (27.1 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]-hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) and N-Boc-L-proline (11.6 mg) in the same manner as describedfor EXAMPLE 71.

MS (FAB⁺) m/z: 643 (MH⁺).

HRMS (FAB⁺) for C₃₃H₃₆FN8O₅ (MH⁺): calcd, 643.2793; found, 643.2744.

Step 2.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-[((2S)-pyrrolidin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

The compound of Step 2 in Example 87 (16.8 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S)-1-t-butoxycarbonylpyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(26.9 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 543 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₈H₂₈FN₈O₃ (MH⁺): calcd, 543.2268; found, 543.2243.

EXAMPLE 88

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-[((2 S,4R)-4-hydroxypyrrolidin-2-yl)carbonyl]--azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S,4R)-1-t-Butoxycarbonyl-4-hydroxypyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The compound of Step 1 of Example 88 (28.4 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) and N-Boc-4-hydroxy-L-proline (12.3 mg) in the same manner asdescribed for EXAMPLE 71.

MS (FAB⁺) m/z: 659 (MH⁺).

HRMS (FAB⁺) for C₃₃H₃₆FN₈O₆ (MH⁺): calcd, 659.2742; found, 659.2775.Step 2.

Compound 88 (15.6 mg) was prepared from the compound of Step 1 ofExample 88 (27.4 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 559 (MH⁺).

HRMS (FAB⁺) for C₂₈H₂₈FN₈O₄(MH⁺): calcd, 559.2218; found, 559.2247.

EXAMPLE 89

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-[((2S,4S)-4-fluoropyrrolidin-2-yl)carbonyl]-3-azabicyclo[3.1.1]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

Step 1

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S,4S)-1-t-Butoxycarbonyl-4-fluoropyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The compound of Step 1 of Example 89 (73.6 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(50.0 mg) and N-Boc-(4S)-fluoro-L-proline (31.5 mg) in the same manneras described for EXAMPLE 71.

MS (FAB⁺) m/z: 661 (MH⁺).

HRMS (FAB⁺) for C₃₃H₃₅F₂N₈O₅ (MH⁺): calcd, 661.2698; found, 661.2656.

Step 2.

The compound of Example 89 (44.0 mg) was prepared from the compound ofStep 1 of Example 89 (69.3 mg) in the same manner as described forEXAMPLE 2.

MS (FAB⁺) m/z: 561 (MH⁺).

HRMS (FAB⁺) for C₂₈H₂₇F₂N₈O₃ (MH⁺): calcd, 561.2174; found, 561.2142.

EXAMPLE 90

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxookazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 90 (473 mg) was prepared from1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(600 mg) and5-bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-(t-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-6-yl]pyridine(702 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 636 (MH⁺).

HRMS (FAB⁺) for C₃₂H₃₉FN₇O₆ (MH⁺): calcd, 636.2946; found, 636.2931.

EXAMPLE 91

1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-Amino-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleDihydrochloride.

Title Compound 91 (305 mg) was prepared from1-[5(R)-3-[4-[4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-(t-butoxycarbonyl)-amino-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(397 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 436 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₃FN₇O₂ (MH⁺): calcd, 436.1897; found, 436.1898.

EXAMPLE 92

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-Acetoxyacetyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

To a suspension of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(30.0 mg) in dichloromethane (0.7 mL) was added triethylamine (28 μL)and acetoxyacetyl chloride (7.0 μL) at 0° C., the mixture was stirred atthe same temperature for 1 hour. After dilution of the mixture withwater, the mixture was extracted with dichloromethane. The organicextracts were washed with water and brine, dried over anhydrous sodiumsulfate, filtered, and then concentrated in vacuo. Flash chromatography(silica, dichloromethane:methanol=10:1) of the residue gave the titlecompound of 92 (34.7 mg).

MS (FAB⁺) m/z: 546 (MH⁺).

HRMS (FAB⁺) for C₂₇H₂₅FN₇O₅ (MH⁺): calcd, 546.1901; found, 546.1888.

EXAMPLE 93

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-hydroxyacetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

To a solution of1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-acetoxyacetyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(255 mg) in methanol (4.5 mL) and tetrahydrofuran (1.3 mL) was addedpotassium carbonate (130 mg) at room temperature, the mixture wasstirred at the same temperature for 2 hours, and concentrated in vacuo.After dilution of the residue with dichloromethane-methanol (5:1)solution, the mixture was washed with brine. The organic extracts weredried over anhydrous magnesium sulfate, filtered, and then concentratedin vacuo. Flash chromatography (silica, dichloromethane:methanol=5:1) ofthe residue gave the title compound of Example 93 (137 mg).

MS (FAB⁺) m/z: 504 (MH⁺).

HRMS (FAB⁺) for C₂₅H₂₃FN₇O₄ (MH⁺): calcd, 504.1796; found, 504.1800.

EXAMPLE 94

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-dichlorocyclopropane)-1-carboxamideDiastereomer A and Diastereomer B.

Title Compound 94 (diastereomer A: 100 mg, diastereomer B: 76.6 mg) wereprepared from5(S)-aminomethyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(269 mg) and 2,2-dichlorocyclopropanecarboxylic acid (110 mg) in thesame manner as described for EXAMPLE 71.

diastereomer A (less polar):

MS (FAB⁺) m/z: 630 (MH⁺).

diastereomer B (more polar):

MS (FAB⁺) m/z: 630 (MH⁺).

EXAMPLE 95

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-dichlorocyclopropane)-1-carboxamideDiastereomer A′. Title Compound 95 (diastereomer A′: 78.9 mg) wasprepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-dichlorocyclopropane)-1-carboxamide(diastereomer A: 97.0 mg) in the same manner as described for EXAMPLE49.

MS (FAB⁺) m/z: 530 (MH⁺).

HRMS (FAB⁺) for C₂₅H₂₃C₁₂FN₅O₃(MH⁺): calcd, 530.1162; found, 530.1198.

EXAMPLE 96

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-dichlorocyclopropane)-1-carboxamideDiastereomer B′. Title Compound 96 (diastereomer B′: 57.2 mg) wasprepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-dichlorocyclopropane)-1-carboxamide(diastereomer B: 73.0 mg) in the same manner as described for EXAMPLE49.

MS (FAB⁺) m/z: 530 (MH⁺).

HRMS (FAB⁺) for C₂₅H₂₃C₁₂FN₅O₃ (MH⁺): calcd, 530.1162; found, 530.1137.

EXAMPLE 97

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-difluorocyclopropane)-1-carboxamide Diastereomer Cand Diastereomer D.

Title Compound 97 (diastereomer C: 125 mg, diastereomer D: 125 mg) wereprepared from5(S)-aminomethyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(300 mg) and 2,2-difluorocyclopropanecarboxylic acid (96.5 mg) in thesame manner as described for EXAMPLE 71.

EXAMPLE 98

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-difluorocyclopropane)-1-carboxamideDiastereomer C′. Title Compound 98 (diastereomer C′: 75.8 mg) wasprepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-difluorocyclopropane)-1-carboxamide(diastereomer C: 122 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) m/z: 498 (MH⁺).

HRMS (FAB⁺) for C₂₅H₂₃F₃N₅O₃ (MH⁺): calcd, 498.1753; found, 498.1783.

EXAMPLE 99

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-difluorocyclopropane)-1-carboxamideDiastereomer D′.

Title Compound 99 (diastereomer D′: 62.2 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-difluorocyclopropane)-1-carboxamide(diastereomer D: 122 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) m/z: 498 (MH⁺).

HRMS (FAB⁺) for C₂₅H₂₃F₃N₅O₃ (MH⁺): calcd, 498.1753; found, 498.1740.

EXAMPLE 100

O-Methyl-N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]carbamate.

Title Compound 100 (53.2 mg) was prepared from5(S)-aminomethyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(200 mg) and methyl chloroformate (37 μL) in the same manner asdescribed for EXAMPLE 92.

MS (FAB⁺) m/z: 552 (MH⁺).

EXAMPLE 101

O-Methyl-N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]carbamate.

Title Compound 101 (32.7 mg) was prepared from O-methylN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]carbamate(50.0 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) m/z: 452 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₃FNSO₄ (MH⁺): calcd, 452.1734; found, 452.1729.

EXAMPLE 102

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3,6-Dicyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 102 (12.2 mg) was prepared from1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]-hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(15.0 mg) in the same manner as described for EXAMPLE 79.

MS (FAB⁺) m/z: 489 (MH⁺).

HRMS (FAB⁺) for C₂₄H₁₉F₂N₈O₂ (MH⁺): calcd, 489.1599; found, 489.1634.

EXAMPLE 103

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 103 (14.8 mg) was prepared from1-[5(R)-3-[4-[4-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(15.0 mg) in the same manner as described for EXAMPLE 78.

MS (FAB⁺) m/z: 478 (MH⁺).

HRMS (FAB⁺) for C₂₄H₂₂F₂N₇O₂ (MH⁺): calcd, 478.1803; found, 478.1825.

EXAMPLE 104

1-[5(R)-3-[3-Fluoro-4-[2-[(1α,5α,6β)-6-hydroxymethyl-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 104 (73.2 mg) was prepared from1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(83.4 mg) and5-bromo-2-[(1α,5α,6β-6-hydroxymethyl-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(58.0 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 452 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₃FN₅O₄ (MH⁺): calcd, 452.1734; found, 452.1735.

EXAMPLE 105

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-4-fluoro-1,2,3-triazole.

Title Compound 105 (101 mg) was prepared from4-fluoro-1-[5(R)-3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(125 mg) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(122 mg) in the same manner as described for EXAMPLE 31.

MS (FAB⁺) m/z: 465 (MH⁺).

HRMS (FAB⁺) for C₂₃H₁₉F₂N₆O₃ (MH⁺): calcd, 465.1487; found, 465.1514.

EXAMPLE 106

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-4-fluoro-1,2,3-triazole.

Title Compound 106 (301 mg) was prepared from4-fluoro-1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(370 mg) and5-bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridine(332 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 564 (MH⁺).

HRMS (FAB⁺) for C₂₈H₂₈F₂N₇O₄ (MH⁺): calcd, 564.2171; found, 564.2168.

EXAMPLE 107

1-[5(R)-3-[4-[2-[(1α,5α,β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-4-fluoro-1,2,3-triazoleHydrochloride.

Title Compound 107 (231 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6α)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-4-fluoro-1,2,3-triazole(290 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 464 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₃H₂₀F₂N₇O₂ (MH⁺): calcd, 464.1647; found, 464.1645.

EXAMPLE 108

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-5-fluoro-1,2,3-triazole.

Title Compound 108 (169 mg) was prepared from1-[5(R)-3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-5-fluoro-1,2,3-triazole(150 mg) and5-bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo-[3.1.0]hexan-6-yl]pyridine(202 mg) in the same manner as described for EXAMPLE 31.

MS (FAB⁺) m/z: 564 (MH⁺).

HRMS (FAB⁺) for C₂₈H₂₈F₂N₇O₄ (MH⁺): calcd, 564.2171; found, 564.2189.

EXAMPLE 109

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-5-fluoro-1,2,3-triazoleHydrochloride.

Title Compound 109 (118 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-5-fluoro-1,2,3-triazole(151 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 464 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₃H₂₀F₂N₇O₂ (MH⁺): calcd, 464.1647; found, 464.1679.

EXAMPLE 110

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-(4-t-Butoxycarbonylpiperazin-1-yl)acetyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title compound 110 (60.7 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(50.0 mg) and 1-t-butoxycarbonylpiperazine (62.6 mg) in the same manneras described for EXAMPLE 78.

MS (FAB⁺) m/z: 672 (MH⁺).

HRMS (FAB⁺) for C₃₄H₃₉FN₉O₅ (MH⁺): calcd, 672.3058; found, 672.3040.

EXAMPLE 111

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-(piperazin-1-yl)acetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleDihydrochloride.

Title Compound 111 (57.0 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-(4-t-butoxycarbonylpiperazin-1-yl)-acetyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(59.7 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 572 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₉H₃₁FN₉O₃ (MH⁺): calcd, 572.2534; found, 572.2535.

EXAMPLE 112

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]thiophen-4-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 112 (261 mg) was prepared from1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(388 mg) and4-bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]thiophene(270 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 452 (MH⁺).

HRMS (FAB⁺) for C₂₂H₁₉FN₅O₃S (MH⁺): calcd, 452.1193; found, 452.1180.

EXAMPLE 113

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-(piperidin-1-yl)acetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 113 (15.7 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) and piperidine (17.8 μL) in the same manner as described forEXAMPLE 84.

MS (FAB⁺) m/z: 571 (MH⁺).

HRMS (FAB⁺) for C₃₀H₃₂FN₈O₃ (MH⁺): calcd, 571.2581; found, 571.2579.

EXAMPLE 114

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-(pyrrolidin-1-yl)acetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 114 (20.7 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) and pyrrolidine (15 μL) in the same manner as described forEXAMPLE 84.

MS (FAB⁺) m/z: 557 (MH⁺).

HRMS (FAB⁺) for C₃₀H₃₂FN₈O₃ (MH⁺): calcd, 557.2425; found, 557.2467.

EXAMPLE 115

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-(4-dimethylaminopiperidin-1-yl)acetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 115 (22.0 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) and 4-dimethylaminopiperidine dihydrochloride (36.2 mg) in thesame manner as described for EXAMPLE 84.

MS (FAB⁺) m/z: 614 (MH⁺).

HRMS (FAB⁺) for C₃₂H₃₇FN₉O₃ (MH⁺): calcd, 614.3003; found, 614.3049.

EXAMPLE 116

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-[((2S)-pyrrolidin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S)-1-t-Butoxycarbonylpyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazoldin-5-ylmethyl]-1,2,3-triazole.

The compound of Step 1 of Example 116 (13.3 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]-hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(10.0 mg) and N-Boc-L-proline (5.6 mg) in the same manner as describedfor EXAMPLE 71

MS (FAB⁺) m/z: 661 (MH⁺).

HRMS (FAB⁺) for C₃₃H₃₅F₂N₈O₅ (MH⁺): calcd, 661.2698; found, 661.2691.

Step 2.

Title Compound 116 (8.4 mg) was prepared from the compound of Step 1 oftitle Example 116 (13.3 mg) in the same manner as described for andEXAMPLE 2.

MS (FAB⁺) m/z: 561 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₈H₂₇F₂N₈O₃ (MH⁺): calcd, 561.2174; found, 561.2220.

EXAMPLE 117

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-[((2S,4R)-4-hydroxypyrrolidin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole Hydrochloride.

Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S,4R)-1-t-Butoxycarbonyl-4-hydroxypyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The compound of Step 1 of Example 117 (12.9 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(10.0 mg) and N-Boc-4-hydroxy-L-proline (6.0 mg) in the same manner asdescribed for EXAMPLE 71.

MS (FAB⁺) m/z: 677 (MH⁺).

HRMS (FAB⁺) for C₃₃H₃₅F₂N₈O₆ (MH⁺): calcd, 677.2698; found, 677.2691.

Step 2.

Title Compound 117 (2.7 mg) was prepared from the compound of Step 1 ofExample 117 (11.7 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 577 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₈H₂₇F₂N₈O₄ (MH⁺): calcd, 577.2123; found, 577.2123.

EXAMPLE 118

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-[((2S,4S)-4-fluoropyrrolidin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleHydrochloride.

Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[((2S,4S)-1-t-Butoxycarbonyl-4-fluoropyrrolidin-2-yl)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The compound of Step 1 of Example 118 (12.8 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(10.0 mg) and N-Boc-(4S)-fluoro-L-proline (6.0 mg) in the same manner asdescribed for EXAMPLE 71.

MS (FAB⁺) m/z: 679 (MH⁺).

HRMS (FAB⁺) for C₃₃H₃₄F₃N₈O₅ (MH⁺): calcd, 679.2604; found, 679.2625.

Step 2.

Title Compound 118 (8.8 mg) was prepared from the compound of Step 1 ofExample 118 (12.6 mg) EXAMPLE 2.

MS (FAB⁺) m/z: 579 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₈H₂₆F₃N₈O₃ (MH⁺): calcd, 579.2080; found, 579.2055.

EXAMPLE 119

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Amino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-Butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The compound of Step 1 of Example 119 (9.8 mg) was prepared from1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(22.3 mg) and5-bromo-2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridine(18.4 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 553 (MH⁺).

HRMS (FAB⁺) for C₂₇H₃₀FN₆O₄S (MH⁺): calcd, 553.2033; found, 553.2039.

Step 2.

Title Compound 119 (1.2 mg) was prepared from the compound of Step 1 ofExample 119 (4.0 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) m/z: 453 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₂FN₆O₂S (MH⁺): calcd, 453.1509; found, 453.1520.

EXAMPLE 120

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Amino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-Oxide Diastereomer E′ and Diastereomer F′.

Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-Butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-Oxide Diastereomer E and Diastereomer F.

The compound of Step 1 of Example 120 diastereomer E (4.8 mg) anddiastereomer F (10.2 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) in the same manner as described for EXAMPLE 58.

Diastereomer E (less polar):

MS (FAB⁺) m/z: 569 (MH⁺).

HRMS (FAB⁺) for C₂₇H₃₀FN₆O₅S (MH⁺): calcd, 569.1982; found, 569.1945.

Diastereomer F (more polar):

MS (FAB⁺) m/z: 569 (MH⁺).

HRMS (FAB⁺) for C₂₇H₃₀FN₆O₅S (MH⁺): calcd, 569.1982; found, 569.1947.

Step 2.

Title Compound 120 diastereomer E′ (2.4 mg) was prepared from thecompound of Step 1 of Example 120 diastereomer E (3.7 mg) in the samemanner as described for EXAMPLE 49.

MS (FAB⁺) m/z: 469 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₀FN₆O₂S (MH+): calcd, 469.1458; found, 469.1411.

EXAMPLE 121

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Amino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-Dioxide.

Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-Butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-Dioxide.

The compound of Step 1 of Example 121 (10.6 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) in the same manner as described for EXAMPLE 59.

MS (FAB⁺) m/z: 585 (MH⁺).

HRMS (FAB⁺) for C₂₇H₃₀FN₆O₆S (MH⁺): calcd, 585.1932; found, 585.1923.

Step 2.

Title Compound 121 (2.3 mg) was prepared from the compound of Step 1 ofExample 121 (3.0 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) mlz: 485 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₂FN₆O₄S (MH⁺): calcd, 485.1407; found, 485.1397.

EXAMPLE 122

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Amino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-Butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The compound of Step 1 of Example 122 (141 mg) was prepared from1-[5(R)-3-(3,5-difluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(188 mg) and5-bromo-2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridine(200 mg) in the same manner as described for EXAMPLE 31.

MS (FAB⁺) m/z: 571 (MH⁺).

HRMS (FAB⁺) for C₂₇H₂₉F₂N₆O₄S (MH⁺): calcd, 571.1939; found, 571.1899.

Step 2.

Title Compound 122 (4.2 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(10.0 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) m/z: 471 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₁F₂N₆O₂S (MH⁺): calcd, 471.1415; found, 471.1436.

EXAMPLE 123

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Amino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-Oxide Diastereomer G′ and Diastereomer H′.

Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-Butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-Oxide Diastereomer G and Diastereomer H.

The compound of Step 1 of Example 123 diastereomer G (10.2 mg) anddiastereomer H (18.6 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(30.0 mg) in the same manner as described for EXAMPLE 58.

Diastereomer G (less polar):

MS (FAB⁺) m/z: 587 (MH⁺).

HRMS (FAB⁺) for C₂₇H₂₉F₂N₆O₅S (MH⁺): calcd, 587.1888; found, 587.1860.

Diastereomer H (more polar):

MS (FAB⁺) m/z: 587 (MH⁺).

HRMS (FAB⁺) for C₂₇H₂₉F₂N₆O₅S (MH⁺): calcd, 587.1888; found, 587.1921.

Step 2.

Title Compound 123 diastereomer G′ (0.8 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazolediastereomer G (2.2 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) m/z: 487 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₁F₂N₆O₃S (MH⁺): calcd, 487.1364; found, 487.1348.

EXAMPLE 124

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Amino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-Dioxide.

Step 1.

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-Butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-Dioxide.

The compound of Step I of Example 124 (19.2 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) in the same manner as described for EXAMPLE 59.

MS (FAB⁺) m/z: 603 (MH⁺).

HRMS (FAB⁺) for C₂₇H₂₉F₂N₆O₆S (MH⁺): calcd, 603.1837; found, 603.1873.

Step 2.

Title Compound 124 (2.7 mg) was prepared from the compound of Step 1 ofExample 124 (4.0 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) m/z: 503 (MH⁺).

HRMS (FAB⁺) for C₂₂H₂₁F₂N₆O₄S (MH⁺): calcd, 503.1313; found, 503.1306.

EXAMPLE 125

5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-one.

Title Compound 125 (47.8 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-5-hydroxymethyloxazolidin-2-one(50.0 mg) in the same manner as described for EXAMPLE 66.

MS (FAB⁺) m/z: 580 (MH⁺).

HRMS (FAB⁺) for C₂₉H₂₈F₂N₅O₆ (MH⁺): calcd, 580.2008; found, 580.1965.

EXAMPLE 126

5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-oneHydrochloride.

Title Compound 126 (26.5 mg) was prepared from5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-5-[(isoxazol-3-yl)oxy]methyloxazolidin-2-one(47.0 mg) in the same manner as described for EXAMPLE 2.

MS (FAB⁺) m/z: 480 (MH⁺) (as free base).

HRMS (FAB⁺) for C₂₄H₂₀F₂N₅O₄ (MH⁺): calcd, 480.1483; found, 480.1449.

EXAMPLE 127

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-(4-methylpiperazin-1-yl)acetyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 127 (17.9 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-pyridin-5-yl]-3-fluoropheny]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) and N-methylpiperazine (20 μL) in the same manner as describedfor EXAMPLE 84.

MS (FAB⁺) m/z: 586 (MH⁺).

HRMS (FAB⁺) for C₃₀H₃₃FN₉O₃ (MH⁺): calcd, 586.2690; found, 586.2642.

EXAMPLE 128

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 128 (201 mg) was prepared from1-[5(R)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(263 mg) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-thiabicyclo-[3.1.0]hexan-6-yl]pyridine(200 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 445 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₁N₆O₂S (MH⁺): calcd, 445.1447; found, 445.1434.

EXAMPLE 129

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-Oxide.

Title Compound 129 (21.9 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(22.3 mg) in the same manner as described for EXAMPLE 58.

MS (FAB⁺) m/z: 461 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₁N₆O₃S (MH⁺): calcd, 461.1396; found, 461.1390.

EXAMPLE 130

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-Dioxide.

Title Compound 130 (18.2 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(22.3 mg) in the same manner as described for EXAMPLE 58.

MS (FAB⁺) m/z: 477 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₁N₆O₄S (MH⁺): calcd, 477.1345; found, 477.1329.

EXAMPLE 131

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 131 (142 mg) was prepared from1-[5(R)-3-[3,5-difluoro-4(trifluoromethanesulfonyl)-oxyphenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(254 mg) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridine(200 mg) in the same manner as described for EXAMPLE 31.

MS (FAB⁺) m/z: 481 (MH⁺).

HRMS (FAB⁺) for C₂₃H₁₉F₂N₆O₂S (MH⁺): calcd, 481.1258; found, 481.1241.

EXAMPLE 132

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS-Oxide.

Title Compound 132 (18.5 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) in the same manner as described for EXAMPLE 58.

MS (FAB⁺) m/z: 497 (MH⁺).

HRMS (FAB⁺) for C₂₃H₁₉F₂N₆O₃S (MH⁺): calcd, 497.1207; found, 497.1251.

EXAMPLE 133

1-[5(R)-3-[4-[2-[(1α5,α,6β)-6-Cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleS,S-Dioxide.

Title Compound 133 (18.9 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) in the same manner as described for EXAMPLE 58.

MS (FAB⁺) m/z: 513 (MH⁺).

HRMS (FAB⁺) for C₂₃H₁₉F₂N₆O₄S (MH⁺): calcd, 513.1157; found, 513.1181.

EXAMPLE 134

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-(1,3-diacetoxypropan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

To a solution of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-(1,3-dihydroxypropan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(7.7 mg) in dichloromethane (0.2 mL) was added acetic anhydride at roomtemperature, the mixture was stirred at the same temperature for 5hours. To the mixture was added 4-(dimethylamino)pyridine (9.0 mg), themixture was stirred at room temperature for 1 hour and concentrated invacuo. Preparative thin-layer chromatography (silica, dichloromethane:methanol=10:1) of the residue gave title compound 134 (5.8 mg).

MS (FAB⁺) m/z: 604 (MH⁺).

HRMS (FAB+) for C₃₀H₃₁FN₇O₆(MH⁺): calcd, 604.2320; found, 604.2300.

EXAMPLE 135

1-[5(R)-3-[4-[2-[(1α,5α,6β)-3-[(3R,4S)-1-Azabicyclo[2.2.1]hepan-3-yl]carbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Title Compound 135 (3.9 mg) was prepared from1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(20.0 mg) and (3R,4S)-1-azabicycloheptane-3-carboxylic acidhydrochloride (9.5 mg) in the same manner as described for EXAMPLE 71.

MS (FAB⁺) m/z: 569 (MH⁺).

HRMS (FAB⁺) for C₃₀H₃₀FN₈O₃ (MH⁺): calcd, 569.2425; found, 569.2380.

EXAMPLE 136

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-(pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

A suspension of1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(50.0 mg) and 2-pyridyl trifluoromethnesulfonate (0.86 mL) indiisopropylethylamine (0.2 mL) was stirred at 90° C. for 44 hours. Flashchromatography (silica, ethyl acetate:methanol=5:1) of the mixture gavetitle compound 136 (18.6 mg).

MS (FAB⁺) m/z: 523 (MH⁺).

HRMS (FAB⁺) for C₂₈H₂₄FN₈O₂(MH⁺): calcd, 523.2006; found, 523.1978.

EXAMPLE 137

5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazol-3-yl)]aminomethyloxazolidin-2-one.

Title Compound 137 (54.9 mg) was prepared fromN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one(50.0 mg) in the same manner as described for EXAMPLE 67.

MS (FAB⁺) m/z: 679 (MH⁺).

HRMS (FAB⁺) for C₃₄H₃₇F₂N₆O₇ (MH⁺): calcd, 679.2692; found, 679.2672.

EXAMPLE 138

5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-5-[N-(isoxazol-3-yl)]aminomethyloxazolidin-2-oneHydrochloride.

Title Compound 138 (20.7 mg) was prepared from5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3,5-difluorophenyl]-5-[N-(t-butoxycarbonyl)-N-(isoxazol-3-yl)]aminomethyloxazolidin-2-one(51.8 mg) in the same manner as described for EXAMPLE 2.

¹H NMR (DMSO-d6) δ 3.03-3.09 (m, 2H), 3.40-3.47 (m, 4H), 3.85 (dd, J=9.2Hz, 6.1 Hz, 1H), 3.90-4.00 (m, 2H), 4.20(t, J=9.2 Hz, 1H), 4.90-4.98 (m,1H), 6.00 (d, J=1.8 Hz, 1H), 6.57 (t, J=6.1 Hz, 1H), 7.45-7.53 (m, 2H),7.72 (d, J=7.9 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H), 8.39 (d, J=1.8 Hz, 1H),8.64 (s, 1H).

EXAMPLE 139

1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-(thiatriazol-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

To a solution of 1,1′-thiocarbonyldiimidazole (21.6 mg) in acetonitrile(1.0 mL) was added1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(50.0 mg) at room temperature, the mixture was stirred at the sametemperature for 1 hour. To the mixture was added iodomethane (67.9 μL),the mixture was stirred at room temperature for overnight, andconcentrated in vacuo. A suspension of the residue and sodium azide(21.3 mg) in acetonitrile (1.0 mL) was stirred at room temperature forovernight. After dilution of the mixture with water, the insolublematerials were collected by filtration. Preparative thin-layerchromatography (silica, dichloromethane: methanol =10:1) of theinsoluble materials title compound 139 (13.7 mg).

MS (FAB⁺) m/z: 531 (MH⁺).

HRMS (FAB⁺) for C₂₄H₂₀FN₁₀O₂S (MH⁺): calcd, 531.1475; found, 531.1466.

EXAMPLE 140

N-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide.

Step 1.

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide.

A mixture of5(S)-aminomethyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(100 mg), ethyl dithioacetate (28.0 μL), triethylamine (62.2 μL), andtetrahydrofuran (3 mL) was stirred at room temperature for overnight andconcentrated in vacuo Flash chromatography (silica,dichloromethane:methanol=10:1) of the residue gaveN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide(82.0 mg).

MS (FAB⁺) m/z: 552 (MH⁺).

Step 2.

Title Compound 140 (46.2 mg) was prepared from the compound of Step 1 ofExample 140 (77.0 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) m/z: 452 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₃FN₅O₂S (MH⁺): calcd, 452.1557; found, 452.1531.

EXAMPLE 141

O-MethylN-[5(S)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate.

Step 1.

N-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]isothiocyanate.

To a solution of5(S)-aminomethyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(150 mg) in tetrahydrofuran (2.0 mL) was added carbon disulfide (36.6μL) and triethylamine (42.4 μL) at 0° C., the mixture was stirred at thesame temperature for 4 hours. To the mixture was added ethylchloroformate (29.1 μL) at 0° C., the mixture was stirred at the sametemperature for 30 minutes and concentrated in vacuo. Treatment of theresidue with water gave crude product. A solution of the crude productin dichloromethane was dried over anhydrous sodium sulfate, filtered,and then concentrated in vacuo. Flash chromatography (silica, ethylacetate) of the residue gave the compound of Step 1 of Example 141 (125mg).

MS (FAB⁺) m/z: 536 (MH⁺).

Step 2.

O-MethylN-[5(S)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate.

To a solution of sodium methoxide in methanol (prepared from sodiumhydride (26.5 mg) and methanol (1.0 mL)) was added a suspension of thecompound of Step 1 of Example 141 (119 mg) in methanol (1.0 mL) at 0°C., the mixture was stirred at room temperature for 5 hours andconcentrated in vacuo. After dilution of the residue with water, themixture was extracted with dichloromethane-methanol (10:1). The organicextracts were dried over anhydrous sodium sulfate, filtered, and thenconcentrated in vacuo. Flash chromatography (silica, dichloromethane:ethyl acetate=1:1) of the residue gave the compound of Step 2 of Example141 (93.5 mg).

MS (FAB⁺) m/z: 568 (MH⁺).

Step 3.

Title Compound 141 (43.6 mg) was prepared from the compound of Step 2 ofExample 141 (85.0 mg) in the same manner as described for EXAMPLE 49.

MS (FAB⁺) n/z: 468 (MH⁺).

HRMS (FAB⁺) for C₂₃H₂₃FN₅O₃S (MH⁺): calcd, 468.1506; found, 468.1524.

REFERENCE EXAMPLE 1

N-[5(S)-3-[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

The mixture ofN-[5(S)-3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(2.00 g), bis(pinacolato)diboron (1.61 g), potassium acetate (1.56 g)and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride-dichloromethane adduct (432 mg) in dimethyl sulfoxide (50 mL)was heated at 80° C. for 1 hour. The mixture was diluted with water andextracted with ethyl acetate. The organic extracts were washed withbrine, dried over anhydrous magnesium sulfate, and then concentrated invacuo. Flash chromatography (silica, ethyl acetate:acetone=9:1) of theresidue gaveN-[5(S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(889 mg).

MS (EI⁺) m/z: 378 (M⁺).

HRMS (EI⁺) for C₁₈H₂₄BFN₂O₅ (M⁺): calcd, 378.1762; found, 378.1779.

REFERENCE EXAMPLE 2

N-[5(S)-3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

Reference Example 2 (92.5 mg) was prepared fromN-[5(S)-3-(4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (108 mg)and bis(pinacolato)diboron (855 mg) in the same manner as described forREFERENCE EXAMPLE 1.

MS (EI⁺) m/z: 360 (M⁺).

HRMS (EI⁺) for C₁₈H₂₅BN₂O₅ (M⁺): calcd, 360.1857; found, 360.1875.

REFERENCE EXAMPLE 3

1-[5(R)-3-[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Reference Example 3 (1.53 g) was prepared from1-[5(R)-3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(2.69 g) and bis(pinacolato)diboron (1.86 g) in the same manner asdescribed for REFERENCE EXAMPLE 1.

MS (EI⁺) m/z: 388 (M⁺).

HRMS (EI⁺) for C₁₈H₂₂BFN₄O₄(M⁺): calcd, 388.1718; found, 388.1752.

REFERENCE EXAMPLE 4

1-[5(R)-3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Reference Example 4 (147 mg) was prepared from1-[5(R)-3-(4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole (200mg) and bis(pinacolato)diboron (151 mg) in the same manner as describedfor REFERENCE EXAMPLE 1.

MS (EI⁺) m/z: 370 (M⁺).

HRMS (EI⁺) for C₁₈H₂₃BN₄O₄(M⁺): calcd, 370.1812; found, 370.1814.

REFERENCE EXAMPLE 5

5(R)-5-(t-Butyldimethylsilyloxy)methyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one.

To a solution of5(R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyloxazolidin-2-one (3.00 g)in dichloromethane (30 mL) was added imidazole (1.33 g) andt-butyldimethylsilyl chloride (1.48 g) at 0° C., the mixture was stirredat room temperature for 2 hours. The mixture was washed with water, 2Nhydrochloric acid, saturated sodium hydrogencarbonate solution andbrine, dried over anhydrous magnesium sulfate, and then concentrated invacuo to give Reference Example 5 (3.66 g).

MS (EI⁺) m/z: 451 (M⁺).

HRMS (EI⁺) for C₁₆H₂₃FINO₃Si (M⁺): calcd, 451.0476; found, 451.0511.

REFERENCE EXAMPLE 6

5(R)-5-(t-Butyldimethylsilyloxy)methyl-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]oxazolidin-2-one.

Reference Example 6 (64.4 mg) was prepared from5(R)-5-(t-butyldimethylsilyloxy)methyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one(100 mg) and bis(pinacolato)diboron (67.0 mg) in the same manner asdescribed for Reference Example 1.

MS (CI⁺) m/z: 452 (MH⁺).

HRMS (CI⁺) for C₂₂H₃₆BFNO₅Si (MH⁺): calcd, 452.2440; found, 452.2394.

REFERENCE EXAMPLE 7

3,5-Difluoro-4-(methoxymethyl)oxynitrobenzene.

To a solution of 2,6-difluoro-4-nitrophenol (35.0 g) in dichloromethane(300 mL) was added diisopropylethylamine (50.2 mL) and methoxymethylchloride (17.5 mL) at 0° C., the mixture was stirred at room temperaturefor 2 hours. The mixture was washed with water, 5% sodiumhydrogencarbonate solution and brine, dried over anhydrous magnesiumsulfate, and then concentrated in vacuo. Flash chromatography (silica,hexane:ethyl acetate=9:1) of the residue gave Reference Example 7(35.2g).

¹H NMR (CDCl₃) δ 3.59 (d, J=1.5 Hz, 3H), 5.30 (s, 2H), 7.83-7.91 (m,2H).

REFERENCE EXAMPLE 8

4-Benzyloxycarbonylamino-2,6-difluoro-1-(methoxymethyl)oxybenzene.

A suspension of 3,5-difluoro-4-(methoxymethyl)oxynitrobenzene (35.0 g)and palladium catalyst (10% on charcoal, 3.00 g) in methanol (250 mL) )was hydrogenated at 1 atm for 2 hours at room temperature. Afterfiltration of the catalyst, the filtrate was concentrated in vacuo togive 4-amino-2,6-difluoro-1-(methoxymethyl)oxybenzene. This was used inthe next step without further purification. To a solution of crude4-amino-2,6-difluoro-1-(methoxymethyl)oxybenzene thus obtained intetrahydrofuran (500 mL) was successively added sodium hydrogencarbonate(17.4 g), water (100 mL) and benzyl chloroformate (30.0 g) at 0° C., andthe mixture was stirred at room temperature for 15 minutes. The mixturewas diluted with saturated sodium hydrogencarbonate solution andextracted with ethyl acetate. The organic extracts were washed withbrine, dried over anhydrous magnesium sulfate, and then concentrated invacuo. Flash chromatography (silica, hexane:ethyl acetate=6:1) of theresidue gave Reference Example 8 (49.10 g).

MS (EI⁺) m/z: 323 (M⁺).

HRMS (EI⁺) for C₁₆H₁₅F₂NO₄ (M⁺): calcd, 323.0969; found, 323.0963.

REFERENCE EXAMPLE 9

5(R)-3-[3,5-Difluoro-4-(methoxymethyl)oxyphenyl]-5-hydroxymethyloxazolidin-2-one.

To a solution of4-benzyloxycarbonylamino-2,6-difluoro-1-(methoxymethyl)oxybenzene (46.3g) in dry tetrahydrofuran (400 mL) was added a solution ofn-butyllithium in hexane (1.6 M, 90.0 mL) at −78° C., and the mixturewas stirred at the same temperature for 30 minutes. (R)-Glycidylbutyrate (20.3 mL) was added to the mixture at −78° C. and the mixturewas allowed to stand at room temperature for 3 hours. After quenchingthe reaction with the addition of aqueous ammonium chloride solution,the mixture was extracted with ethyl acetate. The organic extracts werewashed with brine, dried over anhydrous magnesium sulfate, filtered, andthen concentrated in vacuo. To a solution of the residue in methanol(300 mL) was added potassium carbonate (20.0 g), the mixture was stirredat room temperature for 30 minutes, and then concentrated in vacuo.After dilution of the residue with water, the mixture was extracted withethyl acetate. The organic extracts were washed with brine, dried overanhydrous magnesium sulfate, filtered, and then concentrated in vacuo.Flash chromatography (silica, hexane: ethyl acetate =1:4) of the residuegave Reference Example 9 (36.1 g).

MS (EI⁺) m/z: 289 (M⁺).

HRMS (EI⁺) for C₁₂H₁₃F₂NO₅ (M⁺): calcd, 289.0762; found, 289.0743.

REFERENCE EXAMPLE 10

N-[5(S)-3-[3,5-Difluoro-4-(methoxymethyl)oxyphenyl]-2-oxooxazolidin-5-ymethyl]acetamide.To a solution of5(R)-3-[3,5-difluoro-4-(methoxymethyl)oxyphenyl]-5-hydroxymethyloxazolidin-2-one(5.00 g) in dichloromethane (20 mL) were successively addedtriethylamine (4.82 mL) and methanesulfonyl chloride (2.53 mL) at 0° C.,and the mixture was stirred at the same temperature for 1 hour. Themixture was washed with water, dried over anhydrous magnesium sulfate,filtered, and then concentrated in vacuo to give5(R)-3-[3,5-difluoro-4-(methoxymethyl)oxyphenyl]-5-methanesulfonyloxymethyloxazolidin-2-one.This was used in the next step without further purification. The mixtureof crude5(R)-3-[3,5-difluoro-4-(methoxymethyl)oxyphenyl]-5-methanesulfonyloxymethyloxazolidin-2-onethus obtained and sodium azide (3.93 g) in N,N-dimethylformamide (20 mL)was heated at 60° C. for 8 hours, and then concentrated in vacuo. Theresidue was diluted with ethyl acetate and washed with water and brine.The organic extracts were dried over anhydrous magnesium sulfate,filtered, and then concentrated in vacuo to give5(R)-azidomethyl-3-[3,5-difluoro-4-(methoxymethyl)oxyphenyl]oxazolidin-2-one(5.43 g). This was used in the next step without further purification. Asuspension of5(R)-azidomethyl-3-[3,5-difluoro-4-(methoxymethyl)oxyphenyl]oxazolidin-2-one(3.53 g) and Lindlar catalyst (5% palladium on CaCO₃ partially poisonedwith lead, 700 mg) in methanol (110 mL) was hydrogenated at 1 atm for 6hours at room temperature. After filtration of the catalyst, thefiltrate was concentrated in vacuo. To a solution of the residue intetrahydrofuran (15 mL) was added triethylamine (6.30 mL) and aceticanhydride (2.10 mL) at room temperature, and the mixture was stirred atthe same temperature for 2 hours. After quenching the reaction by theaddition of saturated sodium hydrogencarbonate solution, the mixture wasextracted with ethyl acetate. The organic extracts were dried overanhydrous magnesium sulfate, filtered, and then concentrated in vacuo.Flash chromatography (silica, ethyl acetate) of the residue gaveReference Example 10 (3.45 g).

MS (EI⁺) m/z: 330 (M⁺).

HRMS (EI⁺) for C₁₄Hl₆F₂N₂O₅ (M⁺): calcd, 330.1027; found, 330.1001.

REFERENCE EXAMPLE 11

N-[5(S)-3-(3,5-Difluoro-4-hydroxyphenyl)-2-oxooxazolidin-5-ylmethyl]acetamide.

To a solution ofN-[5(S)-3-[3,5-difluoro-4-(methoxymethyl)oxyphenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(200 mg) in methanol (5 mL) was added concentrated hydrochloric acid(0.50 mL), the mixture was stirred at room temperature for 1 day, andthen concentrated in vacuo. Treatment with water of the residue gaveReference Example 11 (144 mg).

MS (EI⁺) m/z: 286 (M⁺).

HRMS (EI⁺) for C₁₂H₁₂F₂N₂O₄ (M⁺): calcd, 286.0765; found, 286.0747.

REFERENCE EXAMPLE 12

N-[5(S)-3-[3,5-Difluoro-4-(trifluoromethanesulfonyl)oxyphenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

To a solution ofN-[5(S)-3-(3,5-difluoro-4-hydroxyphenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(2.70 g) in pyridine (15 mL) was added triflic anhydride (2.38 mL) at 0°C., the mixture was stirred at room temperature for 12 hours. Afterdilution of the mixture with water, the mixture was extracted with ethylacetate. The organic extracts were washed with 5% hydrochloric acid andbrine, dried over anhydrous magnesium sulfate, filtered, and thenconcentrated in vacuo. Flash chromatography (silica, ethylacetate:methanol=19:1) of the residue gave Reference Example 12 (3.48g).

MS (EI⁺) m/z: 418 (M⁺).

HRMS (EI⁺) for C₁₃H₁₁F₅N₂O₆S (M⁺): calcd, 418.0258; found, 418.0210.

REFERENCE EXAMPLE 13

1-[5(R)-3-(3-Fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Step 1.

5(R)-Acetoxymethyl-3-(3-fluorophenyl)oxazolidin-2-one.

To a solution of 5(R)-3-(3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one(5.28 g) in tetrahydrofuran (53 mL) was added triethylamine (3.83 mL),acetic anhydride (2.55 mL) and (4-dimethylamino)pyridine (152 mg), andthe mixture was stirred at room temperature for 1 hour. After quenchingthe reaction by the addition of 1 N hydrochloric acid, the mixture wasextracted with ethyl acetate. The organic extracts were washed withbrine, dried over anhydrous sodium sulfate, filtered, and thenconcentrated in vacuo to give crude5(R)-acetoxymethyl-3-(3-fluorophenyl)oxazolidin-2-one (6.33 g).

Step 2.

5(R)-Acetoxymethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one.

To a solution of 5(R)-acetoxymethyl-3-(3-fluorophenyl)oxazolidin-2-one(6.33 g) in acetic acid (40 mL) was added iodine monochloride (1.91 mL),the mixture was stirred at room temperature for 18 hours, and thenconcentrated in vacuo. The resulting residue was dissolved with ethylacetate, the mixture was washed with aqueous sodium hydrogencarbonatesolution, 20% sodium sulfite solution and brine, dried over anhydroussodium sulfate, filtered, and then concentrated in vacuo to give crude5(R)-acetoxymethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one (9.48 g).

Step 3.

5(R)-3-(3-Fluoro-4-iodophenyl)-5-hydroxymethyloxazolidin-2-one.

To a solution of crude5(R)-acetoxymethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one (9.48 g) inmethanol (95 mL) was added potassium carbonate (6.91 g), and the mixturewas stirred at room temperature for 2.5 hours. After insoluble materialswere filtered off, the filtrate was concentrated in vacuo. The residuewas dissolved with ethyl acetate, the mixture was washed with brine,dried over anhydrous sodium sulfate, filtered, and then concentrated invacuo. After treating of the residue with isopropanol, the resultingprecipitates were collected by filtration to give5(R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyloxazolidin-2-one, and thefiltrate was concentrated in vacuo. Flash chromatography (silica, ethylacetate) of the residue gave further amount of the product (total 6.24g).

MS (EI⁺) m/z: 337 (M⁺).

¹H NMR (CDCl₃) δ 2.15 (t, J=6.4Hz, 1H), 3.74-4.80 (m, 5H), 7.07 (dd,J=8.8, 2.4Hz, 1H), 7.48 (dd, J=10.3, 2.4Hz, 1H), 7.70 (dd, J=8.8, 6.8Hz,1H).

Step 4.

5(R)-Azidomethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one.

To a solution of5(R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyloxazolidin-2-one (2.00 g)in dichloromethane (30 mL) was added triethylamine (1.24 mL) andmethanesulfonyl chloride (551 μL) at 0° C., the mixture was stirred atthe same temperature for 30 minutes. The mixture was washed with icewater, dried over anhydrous magnesium sulfate, filtered, and thenconcentrated in vacuo.

The mixture of the residue and sodium azide (964 mg) inN,N-dimethylformamide (30 mL) was stirred at 80° C. for 2 hours andconcentrated in vacuo. After dilution of the residue with water, themixture was extracted with ethyl acetate. The organic extracts weredried over anhydrous magnesium sulfate, filtered, and then concentratedin vacuo to give5(R)-azidomethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one (2.18 g).

MS (EI⁺) m/z: 361 (M⁺).

HRMS (EI⁺) for C₁₀H₈FIN₄O₂(M⁺): calcd, 361.9676; found, 361.9698.

Step 5.

1-[5(R)-3-(3-Fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

The mixture of5(R)-azidomethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one (2.18 g) and2,5-norbornadiene (6.40 mL) in dioxane (45.6 mL) was stirred at 80° C.for 2 hours, 110° C. for 4 hours, and then concentrated in vacuo to giveReference Example 13 (1.70 g).

MS (EI⁺) m/z: 388 (M⁺).

HRMS (EI⁺) for C₁₂H₁₀FIN₄O₂(M⁺): calcd, 387.9833; found, 387.9835.

REFERENCE EXAMPLE 14

5(R)-Azidomethyl-3-(4-iodophenyl)oxazolidin-2-one.

Reference Example 14 (75.3 g) was prepared from5(R)-3-(4-iodophenyl)-5-hydroxymethyloxazolidin-2-one (70.0 g) in thesame manner as described for REFERENCE EXAMPLE 13.

MS (EI⁺) m/z: 344 (M⁺).

HRMS (EI⁺) for C₁₀H₉₁N₄O₂ (M⁺): calcd, 343.9770; found, 343.9740.

REFERENCE EXAMPLE 15

1-[5(R)-3-(4-Iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Reference Example 15 (62.5 mg) was prepared from5(R)-azidomethyl-3-(4-iodophenyl)oxazolidin-2-one (100 mg) in the samemanner as described for REFERENCE EXAMPLE 13.

MS (EI⁺) m/z: 370 (M⁺).

HRMS (EI⁺) for C₁₂H₁₁N₄O₂ (M⁺): calcd, 369.9927; found, 369.9919.

REFERENCE EXAMPLE 16

5(R)-5-(t-Butyldimethylsilyloxy)methyl-3-(4-iodophenyl)oxazolidin-2-one.

Reference Example 16 (2.66 g) was prepared from5(R)-3-(4-iodophenyl)-5-hydroxymethyloxazolidin-2-one (2.00 g) in thesame manner as described for REFERENCE EXAMPLE 5.

MS (EI⁺) m/z: 433 (M⁺).

HRMS (EI⁺) for C₁₆H₂₄INO₃Si (M⁺): calcd, 433.0570; found, 433.0544.

REFERENCE EXAMPLE 17

cis-N-t-Butoxycarbonylpyrrolidine-3,4-diol.

To a solution of N-t-butoxycarbonyl-3-pyrroline (69.3 g) and NMO (72.2g) in tetrahydrofuran (340 mL), t-butanol (210 mL) and water (100 mL)was added OsO4 (2.5% solution in t-butanol, 4.8 mL), the mixture washeated under reflux for 2.5 hours, and then concentrated in vacuo. Afterdilution of the residue with brine, the mixture was extracted with ethylacetate. The organic extracts were concentrated in vacuo. Flashchromatography (silica, hexane:ethyl acetate=1:1) of the residue gave

Reference Example 17 (55.0g).

MS (FAB⁺) m/z: 204 (MH⁺).

HRMS (FAB⁺) for C₉H₁₈NO₄(MH⁺): calcd, 204.1236; found, 204.1240.

REFERENCE EXAMPLE 18

cis-N-t-Butoxycarbonylpyrrolidine-3,4-cyclic Sulfate.

To a solution of cis-N-t-butoxycarbonylpyrrolidine-3,4-diol (406 mg) andtriethylamine (1.1 mL) in dichloromethane (10 mL) was added thionylchloride (220 μL) at 0° C., the mixture was stirred at the sametemperature for 10 minutes. After quenching the reaction by addition ofwater (1 mL), the mixture was diluted hexane and water. The organicextracts were washed with water, saturated sodium hydrogencarbonatesolution and brine, dried over anhydrous magnesium sulfate, filtered,and then concentrated in vacuo to give crude cyclic sulfite (482 mg). Toa solution of the crude cyclic sulfite (482 mg) in carbon tetrachloride(6 mL), acetonitrile (6 mL), and water (9 mL) was added ruthenium(III)chloride hydrate (6.0 mg) and sodium periodate (856 mg) at 0° C., themixture was stirred at the same temperature for 2 hours. After dilutionof the mixture with hexane and ether, the mixture was extracted withhexane. The organic extracts were washed with brine, dried overanhydrous magnesium sulfate, filtered, and then concentrated in vacuo.Flash chromatography (silica, hexane:ethyl acetate=1:1) of the residuegave Reference Example 18 (438 mg).

MS (FAB⁺) m/z: 266 (MH⁺).

HRMS (FAB⁺) for C₉H₁₆NO₆S (MH⁺): calcd, 266.0698; found, 266.0730.

REFERENCE EXAMPLE 19

5-Bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridine.To a suspension of sodium hydride (60% oil dispersion, 2.24 g) indimethoxyethane (110 mL) was added a solution of5-bromo-2-pyridylacetonitrile (5.0 g) in dimethoxyethane (20 mL) and asolution of cis-N-t-butoxycarbonylpyrrolidine-3,4-cyclic sulfate (7.41g) in dimethoxyethane (20 mL) at 0° C., the mixture was stirred at roomtemperature for 3 hours. After dilution of the mixture with brine, themixture was extracted with ethyl acetate. The organic extracts weredried over anhydrous magnesium sulfate, filtered, and then concentratedin vacuo. Flash chromatography (silica, hexane:ethyl acetate=4:1) of theresidue gave Reference Example 19 (7.50 g).

MS (EI⁺) m/z: 363 (M⁺).

HRMS (EI⁺) for C₁₆H₁₈BrN₃O₂ (M⁺): calcd, 363.0582; found, 363.0582.

REFERENCE EXAMPLE 20

1-Bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorobenzene.

Reference Example 20 (334 mg) was prepared from4-bromo-2-fluorophenylacetonitrile (214 mg) andcis-N-t-butoxycarbonylpyrrolidine-3,4-cyclic sulfate (292 mg) in thesame manner as described for REFERENCE EXAMPLE 19.

MS (FAB+) m/z: 381 (MH⁺).

HRMS (FAB⁺) for C₁₇H₁₉BrFN₂O₂ (MH⁺): calcd, 381.0614; found, 381.0622.

REFERENCE EXAMPLE 21

5-Bromo-2-chloro-3-fluoropyridine.

A suspension of 5-bromo-3-fluoro-2-hydroxypyridine (10.0 g) inphosphoryl chloride (50 mL) was heated at 150° C. for 4 hours. Themixture was poured into ice, the resulting mixture was adjusted to pH 10by addition of potassium carbonate and extracted with dichloromethane.The organic extracts were dried over anhydrous magnesium sulfate,filtered, and then concentrated in vacuo to give Reference Example 21(10.9 g).

MS (EI⁺) m/z: 209 (M⁺).

HRMS (EI⁺) for C₅H₂BrCIFN (M⁺): calcd, 208.9043; found, 208.9064.

REFERENCE EXAMPLE 22

5-Bromo-3-fluoro-2-pyridineacetonitrile.

The mixture of 5-bromo-2-chloro-3-fluoropyridine (700 mg) and potassiumfluoride (773 mg) in dimethyl sulfoxide (14 mL) was heated at 150° C.for 12 hours. To the resulting mixture was added a solution of sodiumanion of t-butyl cyanoacetate [prepared from t-butyl cyanoacetate (1.27g) and sodium hydride (346 mg) in dimethyl sulfoxide (14 mL)] indimethyl sulfoxide (14 mL), the mixture was stirred at room temperaturefor 2.5 days. After dilution of the mixture with saturated ammoniumchloride solution, the mixture was extracted with ethyl acetate. Theorganic extracts were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and then concentrated in vacuo. Flash chromatography(silica, hexane:ethyl acetate=5: 1) of the residue gave crude t-butyl5-bromo-3-fluoro-2-pyridinecyanoacetate. To a solution of the crudet-butyl 5-bromo-3-fluoro-2-pyridinecyanoacetate in acetonitrile (5 mL)was added trifluoroacetic acid (5 mL) at 0° C., the mixture was stirredat room temperature for 2 hours, and poured into ice water and potassiumcarbonate. The mixture was extracted with ethyl acetate. The organicextracts were washed with brine, dried over anhydrous magnesium sulfate,filtered, and then concentrated in vacuo. Flash chromatography (silica,hexane:ethyl acetate=4:1) of the residue gave Reference Example 22 (179mg).

MS (EI⁺) m/z: 214 (M⁺).

HRMS (EI⁺) for C₇H4BrFN₂ (M⁺): calcd, 213.9542; found, 213.9558.

REFERENCE EXAMPLE 23

5-Bromo-2-pyrimidineacetonitrile.

To a suspension of sodium hydride (3.76 g) in dimethyl sulfoxide (200mL) was added t-butyl cyanoacetate (13.9 mL) at 10° C., the mixture wasstirred at room temperature for 1 hour. To the mixture was added5-bromo-2-chloropyrimidine (7.00 g), the mixture was stirred at roomtemperature for 2 hours, and poured into ice water and ammoniumchloride. The mixture was extracted with ethyl acetate. The organicextracts were dried over anhydrous magnesium sulfate, filtered, and thenconcentrated in vacuo to give crude t-butyl5-bromo-2-pyrimidinecyanoacetate. To a suspension of the crude t-butyl5-bromo-2-pyrimidinecyanoacetate (3.9 g) in dichloromethane (75 mL) wasadded trifluoroacetic acid (75 mL) at 0° C., the mixture was stirred atroom temperature for 18 hours, and concentrated in vacuo. After dilutionof the residue with saturated sodium hydrogencarbonate solution, themixture was extracted with ethyl acetate. The organic extracts weredried over anhydrous magnesium sulfate, filtered, and then concentratedin vacuo. Flash chromatography (silica, hexane:ethyl acetate=2:1) of theresidue gave Reference Example 23 (3.71 g).

MS (EI⁺) m/z: 197 (M⁺).

HRMS (EI⁺) for C₆H₄BrN₃ (M⁺): calcd, 196.9589; found, 196.9572.

REFERENCE EXAMPLE 24

1-[5(R)-3-(3,5-Difluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-4-methyl-1,2,3-triazole.

To a solution of5(R)-aminomethyl-3-(3,5-difluoro-4-iodophenyl)oxazolidin-2-one (100 mg)in methanol (2 mL) was added diisopropylethylamine (262 μL) andasym-dichloroacetone tosylhydrazone (108 mg) at 0° C., the mixture wasstirred at room temperature for 20 hours, and concentrated in vacuo.Flash chromatography (silica, ethyl acetate) of the residue gaveReference Example 24 (110 mg).

MS (EI⁺) m/z: 420 (M⁺).

HRMS (EI⁺) for C₁₃H₁₁F₂IN₄O₂(M⁺): calcd, 420.9895; found, 420.9904.

REFERENCE EXAMPLE 25

cis-Tetrahydrofuran-3,4-cyclic Sulfate.

To a suspension of 1,4-anhydroerythritol (5.00 g) in carbontetrachloride (48 mL) was added thionyl chloride (4.2 mL), the mixturewas heated under reflux for 1 hour. The mixture was cooled to 0° C., anddiluted with acetonitrile (48 mL). The mixture was added sodiumperiodate (15.4 g), ruthenium trichloride n-hydrate (49.8 mg), and thenwater at 0° C., the mixture stirred at room temperature for 3 hours.After dilution of the mixture with ether, the mixture was washed withwater. The organic extracts were washed with water, dried over anhydrousmagnesium sulfate, filtered, and then concentrated in vacuo. Flashchromatography (silica, hexane:ethyl acetate=1:1) of the residue gaveReference Example 25 (6.70 g).

MS (CI⁺) m/z: 167 (MH⁺).

HRMS (CI⁺) for C₄H₇O₅S (MH⁺): calcd, 167.0014; found, 166.9993.

REFERENCE EXAMPLE 26

5-Bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine.

Reference Example 26 (187 mg) was prepared from5-bromo-2-pyridylacetonitrile (197 mg) andcis-tetrahydrofuran-3,4-cyclic sulfate (183 mg) in the same manner asdescribed for REFERENCE EXAMPLE 19.

MS (CI⁺) m/z: 265 (MH⁺).

HRMS (CI⁺) for C₁₁H₁₀BrN₂O (MH⁺): calcd, 264.9976; found, 264.9981.

REFERENCE EXAMPLE 27

6-(5-Bromopyridin-2-yl)-(1α,5α,6β)-3-oxabicyclo[3.1.0]hexane-6-carboxamide.

The mixture of5-bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(4.00 g) and 25% sodium hydroxide solution (66 mL) in ethanol (200 mL)was heated under reflux for 6 hours and concentrated in vacuo. Treatmentof the residue with water gave Reference Example 27 (4.20 g).

MS (EI⁺) m/z: 282 (M⁺).

HRMS (EI⁺) for C₁₁H₁₁BrN₂O₂ (M⁺): calcd, 282.0004; found, 281.9966.

REFERENCE EXAMPLE 28

5-Bromo-2-[(1α,5α,5β)-6-t-butoxycarbonylamino-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine.

The mixture of6-(5-bromopyridin-2-yl)-(1α,5α,6β)-3-oxabicyclo[3.1.0]hexane-6-carboxamide(2.50 g) and lead tetraacetate (7.83 g) in t-butanol (125 mL) was heatedunder reflux for 8 hours. After quenching the reaction by addition ofsaturated sodium hydrogencarbonate solution, the mixture was dilutedwith ethyl acetate. After the insoluble materials were filtered off, thefiltrate was extracted with ethyl acetate. The organic extracts werewashed with brine, dried over anhydrous magnesium sulfate, filtered, andthen concentrated in vacuo. Flash chromatography (NH silica,hexane:ethyl acetate=7:3) of the residue gave Reference Example 28 (2.10g).

MS (FAB⁺) m/z: 355 (MH⁺).

HRMS (FAB⁺) for C₁₅H₂₀BrN₂O₃ (MH⁺): calcd, 355.0657; found, 355.0656.

REFERENCE EXAMPLE 29

1-Bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorobenzene.

Reference Example 29 (1.06 g) was prepared from4-bromo-3,5-difluorophenylacetonitrile (1.50 g) andcis-N-t-butoxycarbonylpyrrolidine-3,4-cyclic sulfate (1.89 g) in thesame manner as described for Reference Example 19.

MS (FAB⁺) m/z: 399 (MH⁺).

HRMS (FAB⁺) for C₁₇H₁₈BrF₂N₂O₂ (MH⁺): calcd, 399.0520; found, 399.0522.

REFERENCE EXAMPLE 30

1-Bromo-4-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]benzene.

Reference Example 30 (809 mg) was prepared from4-bromophenylacetonitrile (1.00 g) andcis-N-t-butoxycarbonylpyrrolidine-3,4-cyclic sulfate (1.49 g) in thesame manner as described for Reference Example 19.

MS (FAB⁺) m/z: 363 (MH⁺).

HRMS (FAB⁺) for C₁₇H₂₀BrN₂O₂ (MH⁺): calcd, 363.0708; found, 363.0730.

REFERENCE EXAMPLE 31

5-Bromo-2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridine.

Reference Example 31 (5.5 mg) was prepared from5-bromo-2-pyridylacetonitrile (32.3 mg) andcis-tetrahydrothiophene-3,4-cyclic sulfate (32.9 mg) in the same manneras described for Reference Example 19.

MS (FAB⁺) m/z: 281 (MH⁺).

HRMS (FAB⁺) for C₁₁H₁₀BrN₂S (MH⁺): calcd, 280.9748; found, 280.9743.

REFERENCE EXAMPLE 32

cis-Tetrahydrothiophene-3,4-cyclic sulfate.

To a solution of cis-tetrahydrothiophene-3,4-diol (48.8 mg) andtriethylamine (22.6 μL) in dichloromethane (2 mL) was added a solutionof sulfuryl chloride (48.9 μL) in dichloromethane (0.4 mL) at −78° C.,the mixture was stirred at the same temperature for 1.5 hours. Afterquenching the reaction by addition of ice, the mixture was extractedwith ethyl acetate. The organic extracts were washed with brine, driedover anhydrous sodium sulfate, filtered, and then concentrated in vacuo.Flash chromatography (silica, ethyl acetate) of the residue gaveReference Example 32 (14.6 mg).

MS (EI⁺) m/z: 182 (M⁺).

HRMS (EI⁺) for C₄H₆O₄S₂ (M⁺): calcd, 182.0582; found, 182.0582.

REFERENCE EXAMPLE 33

Step 1.

5-Bromo-2-[(1α,5α,6β)-6-carboxyl-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine.

To a solution of6-(5-bromopyridin-2-yl)-(1α,5α,6β)-3-oxabicyclo[3.1.0]hexane-6-carboxamide(100 mg) in concentrated sulfuric acid (1.0 mL) and water (0.5 mL) wasadded sodium nitrite (73.1 mg) at 0° C., the mixture was stirred at roomtemperature for 30 minutes. After addition of ice water (1.5 mL), themixture was stirred at room temperature for 30 minutes. The mixture wasadjusted to pH 7 by the addition of potassium carbonate at 0° C. Themixture was adjusted to pH 4 by the addition of 5% hydrochloric acid,the mixture was extracted with chloroform. The organic extracts weredried over anhydrous magnesium sulfate, filtered, and then concentratedin vacuo to give5-bromo-2-[(1α,5α,6β)-6-carboxyl-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(87.9 mg).

MS (EI⁺) m/z: 283 (M⁺).

HRMS (EI⁺) for C₁₁H₁₀BrNO₃ (M⁺): calcd, 282.9844; found, 282.9874.

Step 2.

5-Bromo-2-[(1α,5α,6β)-6-hydroxymethyl-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine.

To a solution of5-bromo-2-[(1α,5α,6β)-6-carboxyl-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(150 mg) in tetrahydrofuran (5.3 mL) was added a solution ofdiisobutylalminum hydride in toluene (1.0 M, 1.32 mL) at 0° C., themixture was stirred at room temperature for 1 hour, and stirred at 60°C. for 1 hour. After quenching the reaction by addition of saturatedammonium chloride solution, the mixture was stirred at room temperaturefor 30 minutes. The mixture was extracted with ethyl acetate. Theorganic extracts were dried over anhydrous magnesium sulfate, filtered,and then concentrated in vacuo. Flash chromatography (silica,hexane:ethyl acetate=1:3) of the residue gave5-bromo-2-[(1α,5α,6β)-6-hydroxymethyl-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(62.3 mg).

MS (EI⁺) m/z: 269 (M⁺).

HRMS (EI⁺) for C₁₁H₁₂BrNO₂ (M⁺): calcd, 269.005 1; found, 269.0045.

REFERENCE EXAMPLE 34

4-Bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]thiophene.

Reference Example 34 (104 mg) was prepared from4-bromo-2-thiopheneacetonitrile (100 mg) andcis-tetrahydrofuran-3,4-cyclic sulfate (90.4 mg) in the same manner asdescribed for Reference Example 26.

MS (EI⁺) m/z: 269 (M⁺).

HRMS (EI⁺) for C₁₀H₈BrNOS (M⁺): calcd, 268.9510; found, 268.9519.

REFERENCE EXAMPLE 35

5-Bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-(1-butoxycarbonyl)amino-3-azabicyclo[3.1.0]hexan-6-yl]pyridine.

Step 1.

5-Bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-carbamoyl-3-azabicyclo[3.1.0]hexan-6-yl]pyridine.

A mixture of5-bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridine(4.00 g) and 25% sodium hydroxide solution (70 mL) in ethanol (210 mL)was heated under reflux for 8 hours and concentrated in vacuo. Treatmentof the residue with ice water gave the compound of Step 1 of ReferenceExample 35 (3.88 g).

MS (FAB⁺) m/z: 382 (MH⁺).

HRMS (FAB⁺) for C₁₆H₂₁BrN₃O₃ (MH⁺): calcd, 382.0766; found, 382.0776.

Step 2.

Reference Example 35 (2.42 g) was prepared from the compound of Step 1of Reference Example 35 (3.50 g) in the same manner as described forReference Example 28.

MS (FAB⁺) m/z: 454 (MH⁺).

HRMS (FAB⁺) for C₂₀H₂₉BrN₃O₄ (MH⁺): calcd, 454.1341; found, 454.1323.

REFERENCE EXAMPLE 36

5(R)-5-(t-Butyldimethylsilyloxy)methyl-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one.

Reference Example 36 (5.42 g) was prepared from5(R)-5-(t-butyldimethylsilyloxy)methyl-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]oxazolidin-2-one(5.00 g) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(2.94 g) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 510 (MH⁺).

HRMS (FAB⁺) for C₂₇H₃₃FN₃O₄Si (MH⁺): calcd, 510.2224; found, 510.2204.

REFERENCE EXAMPLE 37

5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one.

To a solution of5(R)-5-(t-butyldimethylsilyloxy)methyl-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(4.75 g) in tetrahydrofuran (93 mL) was added a solution oftetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 11.2 mL) at 0°C., the mixture was stirred at room temperature for 1 hour. Afterquenching the reaction by addition of saturated ammonium chloridesolution, the mixture was extracted with ethyl acetate. The organicextracts were washed with brine, dried over anhydrous magnesium sulfate,filtered, and then concentrated in vacuo. Treatment of the residue withether gave5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one(3.07 g).

MS (EI⁺) m/z: 395 (M⁺).

HRMS (EI⁺) for C₂₁H₁₈FN₃O₄(M⁺): calcd, 395.1281; found, 395.1261.

REFERENCE EXAMPLE 38

5(R)-Azidomethyl-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one.

Reference Example 38 (1.72 g) was prepared from5(R)-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one(1.90 g) in the same manner as described for Reference Example 13.

MS (FAB⁺) m/z: 421 (MH⁺).

HRMS (FAB⁺) for C₂H₁₈FN₆O₃ (MH⁺): calcd, 421.1424; found, 421.1431.

REFERENCE EXAMPLE 39

5(S)-Aminomethyl-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one.

Reference Example 39 (1.40 g) was prepared from5(R)-azidomethyl-3-[4-[2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(1.60 g) in the same manner as described for Reference Example 10.

MS (FAB⁺) m/z: 395 (MH⁺).

HRMS (FAB⁺) for C₂₁H₂₀FN₄O₃ (MH⁺): calcd, 395.1519; found, 395.1513.

REFERENCE EXAMPLE 40

5(R)-5-(t-Butyldimethylsilyloxy)methyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one.

Reference Example 40 (109 mg) was prepared from5(R)-5-(t-butyldimethylsilyloxy)methyl-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]oxazolidin-2-one(100 mg) and5-bromo-2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridine(80.9 mg) in the same manner as described for EXAMPLE 1.

MS (FAB⁺) m/z: 609 (MH⁺).

HRMS (FAB⁺) for C₃₂H₄₂FN₄O₅Si (MH⁺): calcd, 609.2909; found, 609.2886.

REFERENCE EXAMPLE 41

5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one.

Reference Example 41 (3.21 g) was prepared from5(R)-5-(t-butyldimethylsilyloxy)methyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one(4.24 g) in the same manner as described for Reference Example 36.

MS (FAB⁺) m/z: 495 (MH⁺).

HRMS (FAB⁺) for C₂₆H₂₈FN₄O₅ (MH⁺): calcd, 495.2044; found, 495.2048.

REFERENCE EXAMPLE 42

5(R)-Azidomethyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]oxazolidin-2-one.

Reference Example 42 (1.88 g) was prepared from5(R)-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (2.00 g) in the same manner as described for ReferenceExample 13.

MS (FAB⁺) m/z: 520 (MH⁺).

HRMS (FAB⁺) for C₂₆H₂₇FN₇O₄(MH⁺): calcd, 520.2109; found, 520.2137.

REFERENCE EXAMPLE 43

5(S)-Aminomethyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]oxazolidin-2-one.

Reference Example 43 (48.0 mg) was prepared from5(R)-azidomethyl-3-[4-[2-[(1α,5α,6β)-3-t-butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3-fluorophenyl]oxazolidin-2-one(100 mg) in the same manner as described for Reference Example 10.

MS (FAB⁺) m/z: 494 (MH⁺).

HRMS (FAB⁺) for C₂₆H₂₉FN₅O₄ (MH⁺): calcd, 494.2204; found, 494.2197.

REFERENCE EXAMPLE 44

5-Bromo-2-(4-cyanotetrahydropyran-4-yl)pyridine.

A mixture of 5-bromo-2-pyridineacetonitrile (400 mg),triethylbenzylammonium chloride (462 mg), bis(2-bromoethyl)ether (281μL), and 50% sodium hydroxide solution (10 mL) was stirred at 70° C. for1 hour. After decantation of aqueous layer, the residue was diluted withsaturated ammonium chloride solution and extracted with ethyl acetate.The organic extracts were dried over anhydrous magnesium sulfate,filtered, and then concentrated in vacuo. Flash chromatography (silica,hexane:ethyl acetate=7:3) of the residue gave5-bromo-2-(4-cyanotetrahydropyran-4-yl)pyridine (104 mg).

MS (EI⁺) m/z: 266 (M⁺).

HRMS (EI⁺) for C₁₁H₁₁BrN₂O (M⁺): calcd, 266.0055; found, 266.0038.

REFERENCE EXAMPLE 45

5(R)-3-[4-[2-[(1α,5α,6β)-3-t-Butoxycarbonyl-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-3,5-difluorophenyl]-5-hydroxymethyloxazolidin-2-one.

Reference Example 45 (105 mg) was prepared from5(R)-3-(3,5-difluoro-4-iodophenyl)-5-hydroxymethyloxazolidin-2-one (813mg) and5-bromo-2-[(1α,5α,6β)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridine(1.00 g) in the same manner as described for Reference Example 31.

MS (FAB⁺) m/z: 513 (MH⁺).

HRMS (FAB⁺) for C₂₆H₂₇F₂N₄O₅ (MH⁺): calcd, 513.1950; found, 513.1978.

REFERENCE EXAMPLE 46

5(R)-3-(3,5-Difluoro-4-iodophenyl)-5-hydroxymethyloxazolidin-2-one.

Reference Example 46 (1.91 g) was prepared from5(R)-3-(3,5-difluorophenyl)-5-hydroxymethyloxazolidin-2-one (2.00 g) inthe same manner as described for Reference Example 13.

MS (EI⁺) m/z: 354 (M⁺).

HRMS (EI⁺) for C₁₀H₈F₂INO₃ (M⁺): calcd, 354.9517; found, 354.9522.

REFERENCE EXAMPLE 47

5(R)-Azidomethyl-3-(3,5-difluoro-4-iodophenyl)oxazolidin-2-one.

Reference Example 47 (2.44 g) was prepared from5(R)-3-(3,5-difluoro-4-iodophenyl)-5-hydroxymethyl-oxazolidin-2-one(2.30 g) in the same manner as described for REFERENCE EXAMPLE 13.

MS (FAB⁺) m/z: 381 (MH⁺).

HRMS (FAB⁺) for C₁₀H₈F₂IN₄O₂ (MH⁺): calcd, 380.9660; found, 380.9685.

REFERENCE EXAMPLE 48

1-[5(R)-3-(3,5-Difluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Reference Example 48 (876 mg) was prepared from5(R)-azidomethyl-3-(3,5-difluoro-4-iodophenyl)oxazolidin-2-one (875 mg)in the same manner as described for REFERENCE EXAMPLE 13.

MS (EI⁺) m/z: 406 (M⁺).

HRMS (EI⁺) for C₁₂H₉F₂IN₄O₂ (M⁺): calcd, 405.9738; found, 405.9750.

REFERENCE EXAMPLE 49

4-Fluoro-1-[5(R)-3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleand5-Ffluoro-1-[5(R)-3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.A mixture of 5(R)-azidomethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one(700 mg) and 1-fluoro-1-ethenyl phenyl sulfoxide (987 mg) was heated at110° C. for 15 hours. Flash chromatography (silica, toluene:ethylacetate=2:1) of the residue gave4-fluoro-1-[5(R)-3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(125 mg) and5-fluoro-1-[5(R)-3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(258 mg).

4-Fluoro-1-[5(R)-3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole:

MS (EI⁺) m/z: 406 (M⁺).

HRMS (EI⁺) for C₁₂H₉F₂IN₄O₂ (M⁺): calcd, 405.9738; found, 405.9744.

5-Fluoro-1-[5(R)-3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole:

MS (EI⁺) m/z: 406 (M⁺).

HRMS (EI⁺) for C₁₂H₉F₂IN₄O₂ (M⁺): calcd, 405.9738; found, 405.9753.

REFERENCE EXAMPLE 50

4-Fluoro-1-[5(R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole.

Reference Example 50 (380 mg) was prepared from4-fluoro-1-[5(R)-3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole(430 mg) in the same manner as described for Reference Example 1.

MS (FAB⁺) m/z: 407 (MH⁺).

HRMS (FAB⁺) for C₁₈H₂₂BF₂N₄O₄ (MH⁺): calcd, 407.1702; found, 407.1693.

REFERENCE EXAMPLE 51

5-Bromo-2-[(1α,5α,6β)-6-carboxyl-3-thiabicyclo[3.1.0]hexan-6-yl]pyridine.

A mixture of5-bromo-2-[(1α,5α,6β)-6-cyano-3-thiabicyclo[3.1.0]hexan-6-yl]pyridine(1.77 g) and concentrated hydrochloric acid (17 mL) was heated at 80° C.for 70 minutes and concentrated in vacuo. Treatment of the residue withwater gave Reference Example 51 (1.81 g).

MS (FAB⁺) m/z: 299 (MH⁺).

HRMS (FAB⁺) for C₁₁H₁₀BrNO₂S (MH⁺): calcd, 298.9616; found, 298.9612.

REFERENCE EXAMPLE 52

5-Bromo-2-[(1α,5α,6β)-6-t-butoxycarbonylamino-3-thiabicyclo[3.1.0]hexan-6-yl]pyridine.

To a suspension of5-bromo-2-[(1α,5α,6β)-6-carboxyl-3-thiabicyclo[3.1.0]hexan-6-yl]pyridine(760 mg) in toluene (10 mL) was added diphenylphosphoryl azide (0.60 mL)and triethylamine (0.46 mL) at room temperature, the mixture was stirredat the same temperature for 75 minutes. The mixture was washed withwater and brine. The organic extracts were dried over anhydrousmagnesium sulfate, filtered, and then concentrated in vacuo. A solutionof the residue in t-butanol (5 mL) was stirred at 120° C. for 9.5 hoursand concentrated in vacuo. Flash chromatography (silica, hexane:ethylacetate=9:1) of the residue gave Reference Example 52 (502 mg).

MS (FAB⁺) m/z: 371 (MH⁺).

HRMS (FAB⁺) for C₁₅H₂₀BrN₂O₂S (MH⁺): calcd, 371.0429; found, 371.0407.

REFERENCE EXAMPLE 53

5-Bromo-2-pyridylacetonitrile.

Step 1.

t-Butyl (5-Bromo-2(1H)-pyridinylidene)cyanoacetate.

To a suspension of NaH (66.4 g, 60% oil dispersion) in dry DMSO (1.5 L)was added t-butyl cyanoacetate (243 mL) at 18-25° C. for 1 hour, themixture was stirred at room temperature for 2 hours. 2,5-Dibromopyridine(150 g) was added to the resulting mixture, the mixture was stirred at120° C. for 6.5 hours. After cooling, the mixture was poured intosaturated ammonium chloride solution, the resulting precipitates werecollected by filtration, washed with water and cooled EtOH to givet-butyl (5-bromo-2(1H)-pyridinylidene)cyanoacetate (166 g).

¹H NMR (CDCl₃) δ 1.53 (s, 9H), 7.20 (dd, J=9.8, 1.8Hz, 1H), 7.53 (dd,J=9.8, 2.4Hz, 1H), 7.64 (dd, J=6.1, 1.8Hz, 1H), 14.15 (brs, 1H).

Step 2.

Reference Example 53-A suspension of the compound Step 1 of ReferenceExample 53 (120 g) and KSF clay (80 g) in acetonitrile (800 mL) washeated under reflux for 6 hours. After insoluble materials were filteredoff, the filtrate was concentrated in vacuo. Flash chromatography(silica, hexane:ethyl acetate=4:1) of the residue gave Reference Example53 (57.2 g).

MS (EI⁺) m/z: 197 (M⁺).

Antibacterial Activity

The pharmaceutically-acceptable compounds of the present invention areuseful antibacterial agents having a good spectrum of activity in vitroagainst standard bacterial strains, which are used to screen foractivity against pathogenic bacteria. Notably, thepharmaceutically-acceptable compounds of the present invention showactivity against vancomycin-resistant enterococci, streptococciincluding penicillin-resistant S. pneumoniae, methicillin-resistant S.aureus, M catarrhalis, and C. pneumoniae. The antibacterial spectrum andpotency of a particular compound may be determined in a standard testsystem.

The following in vitro results were obtained based on an agar dilutionmethod except for C. pneumoniae. The activity is presented as theminimum inhibitory concentration (MIC).

S. aureus and M. catarrhalis were tested on Mueller-Hinton agar, usingan approximate inoculum of 1×10⁴ cfu/spot an incubation temperature of35° C. for 24 hours. The MIC was defined as the lowest concentration atwhich no visible bacterial growth was observed.

Streptococci and enterococci were tested on Mueller-Hinton agarsupplemented with 5% defibrinated horse blood, using an approximateinoculum of 1×10⁴ cfu/spot an incubation temperature of 35° C. in anatmosphere of 5 % CO₂ for 24 hours. The MIC was defined as the lowestconcentration at which no visible bacterial growth was observed.

C. pneumoniae was tested using minimum essential medium supplementedwith 10 % heat-inactivated fetal bovine serum, 2 mM L-glutamine, 1 mg/mlcycloheximide and non essential amino acid. HeLa 229 cells wereinoculated with 104 inclusion-forming units of C. pneumoniae strain permL. Infected cells were incubated with test compounds in complete mediumat 35° C. in an atmosphere of 5% CO₂ for 72 hours. Cells monolayers werefixed in methanol, stained for chiamydial inclusions with anfluorescein-conjugated anti-Chlamydia monoclonal antibody, and wereobserved with fluorescence microscope. The MIC was defined as the lowestconcentration at which no inclusion was observed.

MIC (μg/ml) Strains example 13 example 15 example 23 LinezolidStaphylococcus aureus Smith 0.125 0.25 0.06 1 CR 0.5 1 0.5 16 MR 0.1250.25 0.06 1 Streptococcus pneumoniae IID553 0.125 0.25 0.06 2 PRQR 0.060.25 0.06 1 Streptococcus pyogenes IID692 0.06 0.25 0.06 1 Enterococcusfaecium VRQR 0.125 0.5 0.06 2 Morcaxella catarrhalis ATCC25238 1 4 0.5 4CR = chloramphenicol resistant MR = methicillin resistant PRQR =penicillin resistant, quinolone resistant VRQR = vancomycin resistant,quinolone resistant NT = not tested

The invention described herein is exemplified by the followingnon-limiting examples. The compound data is designated in accordance toGeneral Guidelines for Manuscript Preparation, J. Org. Chem. Vol. 66,pg. 19A, Issue 1, 2001.

1. A method of treating a bacterial infection in a mammalian patient inneed thereof, comprising administering to said patient an effectiveamount of a compound of formula I wherein the compound of formula I is

its enantiomer, diastereomer, pharmaceutically acceptable salt, hydrateor prodrug thereof wherein: R¹ represents i) hydrogen, ii)(CH₂)_(n)NR₅R₆, iii) CR₇R₈R₉, C(R)₂OR₁₄ or CH₂NHR₁₄, iv) C(═O)R₁₃,C(═NOH)H, C(═NOR₁₃)H, C(═NOR₁₃)R₁₃, C(═NOH)R₁₃, C(═O)N(R₁₃)₂,C(═NOH)N(R₁₃)₂, NHC(═X₁ )N(R₁₃)₂, NRCO₂R, (C═NH)R₇, N(R₁₃)C(═X₁)N(R₁₃)₂,COOR₁₃, SO₂R₁₄, N(R₁₃)SO₂R₁₄ or N(R₁₃)COR₁₄, v) (C₁₋₆alkyl)CN, CN,CH═C(R)₂, (CH₂)_(p)OH, C(═O)CHR₁₃, C(═NR₁₃)R₁₃ or NR₁₀C(═X₁)R₁₃, or vi)C₅₋₁₀ heterocycle optionally substituted with 1-3 groups of R₇, whichmay be attached through either a carbon or a heteroatom; X represents

Y represents NR*, O, CN or S(O)_(p);

represents aryl or heteroaryl, heterocycle, heterocyclyl orheterocyclic; R₃ represents NR(C═X₂)R₁₂, NR*R₁₂, C₆₋₁₀ aryl or—(O)_(n)C₅₋₁₀ heterocyclyl which may be attached through either a carbonor a heteroatom; said aryl and heterocyclyl optionally substituted with1-3 groups of R₇; R₄, R_(4a), R_(4b), and R_(4c) independently representi) hydrogen, ii) halogen, iii) C₁₋₆ alkoxy, or iv) C₁₋₆ alkyl; r and sindependently are 1-3, with the provision that when (R_(4a))_(s) and(R₄)_(r) or (R_(4b)) and (R_(4c))_(s) are attached to an Ar or HAr ringthe sum of r and s is less than or equal to 4; R₅ and R₆ independentlyrepresent i) hydrogen, ii) C₁₋₆ alkyl optionally substituted with 1-3groups of halogen, CN, OH, C₁₋₆ alkoxy, amino, imino, hydroxyamino,alkoxyamino, C₁₋₆ acyloxy, C₁₋₆ alkylsulfenyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl, C₁₋₆dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl, pyridine,5-isoxazolyl, ethylenyloxy, or ethynyl, said phenyl and pyridineoptionally substituted with 1-3 halogen, CN, OH, CF₃, C₁₋₆ alkyl or C₁₋₆alkoxy, iii) C₁₋₆ acyl optionally substituted with 1-3 groups ofhalogen, OH, SH, C₁₋₆ alkoxy, naphthalenoxy, phenoxy, amino, C₁₋₆acylamino, hydroxylamino, alkoxylamino, C₁₋₆ acyloxy, aralkyloxy,phenyl, pyridine, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₁₋₆ hydroxyacyloxy, C₁₋₆ alkylsulfenyl, phthalimido,maleimido, succinimido, said phenoxy, phenyl and pyridine optionallysubstituted with 1-3 groups of halo, OH, CN, C₁₋₆ alkoxy, amino, C₁₋₆acylamino, CF₃ or C₁₋₆ alkyl, iv) C₁₋₆ alkylsulfonyl optionallysubstituted with 1-3 groups of halogen, OH, C₁₋₆ alkoxy, amino,hydroxylamino, alkoxylamino, C₁₋₆ acyloxy, or phenyl; said phenyloptionally substituted with 1-3 groups of halo, OH, C₁₋₆ alkoxy, amino,C₁₋₆ acylamino, CF₃ or C₁₋₆ alkyl, v) arylsulfonyl optionallysubstituted with 1-3 of halogen, C₁₋₆ alkoxy, OH or C₁₋₆ alkyl, vi) C₁₋₆alkoxycarbonyl optionally substituted with 1-3 of halogen, OH, C₁₋₆alkoxy, C₁₋₆ acyloxy or phenyl, said phenyl optionally substituted with1-3 groups of halogen, OH, C₁₋₆ alkoxy, amino, C₁₋₆ acylamino, CF₃ orC₁₋₆ alkyl, vii) aminocarbonyl, C₁₋₆ alkylaminocarbonyl or C₁₋₆dialkylaminocarbonyl, said alkyl groups optionally substituted with 1-3groups of halogen, OH, C₁₋₆ alkoxy or phenyl, viii) 5- to 6-memberedheterocycles optionally substituted with 1-3 groups of halogen, OH, CN,amino, C₁₋₆ acylamino, C₁₋₆ alkylsulfonylamino, C₁₋₆alkoxycarbonylamino, C₁₋₆ alkoxy, C₁₋₆ acyloxy or C₁₋₆ alkyl, said alkyloptionally substituted with 1-3 groups of halogen or C₁₋₆ alkoxy, ix)C₃₋₆ cycloalkylcarbonyl optionally substituted with 1-3 groups ofhalogen, OH, C₁₋₆ alkoxy or CN, x) benzoyl optionally substituted with1-3 groups of halogen, OH, C₁₋₆ alkoxy, C₁₋₆ alkyl, CF₃, C₁₋₆ alkanoyl,amino or C₁₋₆ acylamino, xi) pyrrolylcarbonyl optionally substitutedwith 1-3 of C₁₋₆ alkyl, xii) C₁₋₂ acyloxyacetyl where the acyl isoptionally substituted with amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino,4-morpholino, 4-aminophenyl, 4-(dialkylamino)phenyl or4-(glycylamino)phenyl, or R₅ and R₆ taken together with any interveningatoms can form a 3- to 7-membered heterocyclic ring containing carbonatoms and 1-2 heteroatoms independently chosen from O, S, SO, SO₂, N orNR₈; R₇ represents i) hydrogen, halogen, (CH₂)_(p)C₅₋₁₀ heterocyclyl,CN, CO₂R, CON(R)₂, CHO, (CH₂)₀₋₃NHAc, C(═NOR), OH, C₁₋₆ alkoxy, C₁₋₆alkyl, alkenyl, hydroxy C₁₋₆ alkyl, (CH₂)₁₋₃NHC(O)C₁₋₆ alkyl,(CH₂)₀₋₃N(C₁₋₆ alkyl)₂, NHCO₂R or —OCOC₁₋₆ alkyl, or ii) (CH₂)_(n)amino,(CH₂)_(n)C₁₋₆ alkylamino, C₁₋₆ acylamino, C₁₋₆ dialkylamino,hydroxylamino or C₁₋₂ alkoxyamino, all of which can be optionallysubstituted on the nitrogen with C₁₋₆ acyl, C₁₋₆ alkylsulfonyl or C₁₋₆alkoxycarbonyl, said acyl and alkylsulfonyl optionally substituted with1-2 of halogen or OH; R₈ and R₉ independently represent i) H or CN, ii)C₁₋₆ alkyl optionally substituted with 1-3 halogen, CN, OH, C₁₋₆ alkoxy,C₁₋₆ acyloxy or amino, or iii) phenyl optionally substituted with 1-3groups of halogen, OH or C₁₋₆ alkoxy, or R₇ and R₈ taken together canform a 3- to 7-membered carbon ring optionally interrupted with 1-2heteroatoms chosen from O, S, SO, SO₂, NH and NR₈; X₁ represents O, S orNR₁₃, NCN, NCO₂R₁₆ or NSO₂R₁₄; X₂ represents O, S, NH or NSO₂R₁₄; R₁₀represents hydrogen, C₁₋₆ alkyl or CO₂R₁₅; R₁₂ represents hydrogen, C₁₋₆alkyl, NH₂, OR, CHF₂, CHCl₂, C(R)₂Cl, (CH₂)_(n)SR, (CH₂)_(n)CN,(CH₂)_(n)SO₂R, (CH₂)_(n)S(O)R, C₁₋₆ alkylamino, C₃₋₆ cycloalkyl, C₅₋₁₀heterocyclyl or C₁₋₆ dialkylamino, where said alkyl, and cycloalkyl maybe substituted with 1-3 groups of halo, CN, OH or C₁₋₆ alkoxy, saidheterocyclyl optionally substituted with 1-3 groups of R₇; each R₁₃represents independently hydrogen, C₁₋₆ alkyl, C₆₋₁₀ aryl, NR₅R₆, SR₈,S(O)R₈, S(O)₂ R₈, CN, OH, C₁₋₆ alkylS(O)R, C₁₋₆ alkoxycarbonyl,hydroxycarbonyl, —OCOaryl, C₁₋₆ acyl or C₃₋₇-membered carbon ringoptionally interrupted with 1-4 heteroatoms chosen from O, S, SO, SO₂,NH and NR₈, where said C₁₋₆ alkyl, aryl or C₁₋₆ acyl groups may beindependently substituted with 0-3 halogens, hydroxy, N(R)₂, CO₂R, C₆₋₁₀aryl, C₅₋₁₀ heteroaryl or C₁₋₆ alkoxy groups; when two R₁₃ groups areattached to the same atom or two adjacent atoms they may be takentogether to form a 3- to 7-membered carbon ring optionally interruptedwith 1-2 heteroatoms chosen from O, S, SO, SO₂, NH and NR₈; R representshydrogen or C₁₋₆ alkyl; R* represents hydrogen, CN, C(═O)R₁₄,(CH₂)_(p)CO₂C₁₋₆ alkyl, (CH₂)_(p)C₅₋₁₀heterocyclyl or C₁₋₆ alkyl, saidalkyl and heterocyclyl optionally substituted with 1 to 3 groups of R₇;R₁₄ represents amino, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,(CH₂)_(p)C₅₋₁₀heterocyclyl, C₁₋₆ haloalkyl or phenyl, said alkyl,cycloalkyl, phenyl, heterocyclyl optionally substituted with 1-3 groupof R₇, when R₇ is an amino or hydroxyl group or a nitrogen that formspart of the heterocycle, said amino and hydroxy optionally protectedwith an amino or hydroxy protecting group; R₁₅ represents C₁₋₆ alkyl orbenzyl, said benzyl optionally substituted with 1-3 groups of halo, OH,C₁₋₆ alkoxy, amino, C₁₋₆ acylamino or C₁₋₆ alkyl; R₁₆ representshydrogen, C₅₋₁₀heteroaryl or C₆₋₁₀aryl, said heteroaryl and aryloptionally substituted with 1-3 groups of R₇; p represents 0-2; and nrepresents 0-1, wherein the bacterial infection is selected from thegroup consisting of Staphylococcus aureus, Streptococcus pneumoniae,Streptococcus pyogenes, Enterococcus faecium and Morcaxella catarrhalis.2. The method of claim 1 comprising administering to said patient aneffective amount of one or more of a vitamin selected from the groupconsisting of vitamin B2, vitamin B6, vitamin B 12 and folic acid. 3.The method of claim 1 wherein the compound is of structural formula IV:

or a pharmaceutically acceptable salt thereof, wherein R₁ represents CNor NH₂; Y represents NR*; R₃ represents C₅₋₁₀ heteroaryl containing 1 to4 nitrogen atoms and at least one double bond, which is connectedthrough a bond on any nitrogen and which is optionally substituted with1 to 3 substituents selected from R₇; and R₄ and R_(4a) independentlyrepresent i) hydrogen, ii) halogen, iii) C₁₋₆ alkoxy, or iv) C₁₋₆ alkyl.4. The method of claim 1 wherein the compound is1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-azabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleor a pharmaceutically acceptable salt thereof.
 5. The method of claim 1wherein the compound is1-[5(R)-3-[4-[2-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazoleor a pharmaceutically acceptable salt thereof.
 6. The method of claim 1wherein the compound isN-[5(S)-3-[4-[4-[(1α,5α,6β)-6-Cyano-3-oxabicyclo[3.1.0]hexan-6-yl]pyridin-5-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamideor a pharmaceutically acceptable salt thereof.